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US 20140221426A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2014/0221426 A1 Gerk et al. (43) Pub. Date: Aug. 7, 2014

(54) SELECTIVE METABOLIC APPROACH TO A61K 31/216 (2006.01) INCREASING ORAL BIOAVAILABILITY OF A61K 31/09 (2006.01) PHENYLEPHRINE AND OTHER PHENOLIC A61K 31/05 (2006.01) BIOACTIVITIES A61K 31/353 (2006.01) A61K 31/4525 (2006.01) (71) Applicant: VIRGINIA COMMONWEALTH A61 K 31/3 75 (2006.01) UNIVERSITY, Richmond, VA (US) A61K 31/121 (2006.01) _ _ _ (52) US. Cl. (72) Inventorsl Ph_lll_lP M- Gerk’ Rthmond, VA (Us); CPC ...... A61K 31/137 (2013.01); A61K 31/3 75 Wllllam H- Fa", R10hm°nda VA (Us); (2013.01); A61K 31/235 (2013.01); A61K J"sellh K- thter’ Rlchmond, VA (Us) 31/11 (2013.01); A61K 31/085 (2013.01); _ A61K 31/121 (2013.01); A61K 31/09 (21) APP1~ NO" 14/345,689 (2013.01); A61K31/05 (2013.01); A61K . _ 31/353 (2013.01);A61K31/4525 (2013.01); (22) PCT Filed. Sep. 27, 2012 A61K31/216 (201301) USPC ...... 514/321' 514/653' 514/474' 514/544' ( 86 ) PCT N 0 .: PCT/U52012/057588 ’ ’ 514/456;’ 514/532’ § 371 (0X1),

Related US“ Application Data Presystemic metabolism in intestine of bioactives such as (60) Provisional application No. 61/539,530, ?led on Sep. phenylephrine 1? avoided by administering a Sllbject (human 27, 2011, provisional application No. 61/544,396, 0r 21111111211) the bloactlve(e-g-,Pheny1ephr1ne)1n comblnatlon ?led on Oct 7, 201 1_ With one or more inhibitors of sulfation (e.g., sulfotransferase enzymes aka SULTs). This can also be enhanced be co Publication Classi?cation administering inhibitors of monoamine oxidases aka, MAOs, and uridine diphosphate glucoronysl transferases, aka UGTs. (51) Int. Cl. Preferably the inhibitors are GRAS compounds. The one or A61K 31/137 (2006.01) more inhibitor compounds inhibit the enzymes responsible A61K 31/235 (2006.01) for rapid presystemic metabolism, thus allowing the bioac A61K 31/11 (2006.01) tives (e. g., phenylephrine) to be more readily absorbed intact A61K 31/085 (2006.01) into the circulatory system. Patent Application Publication Aug. 7, 2014 Sheet 1 0f 4 US 2014/0221426 A1

Synthesis of Phenyiephrine 3-O-Sulfate

OH F

NHCH a i F o 3 1.TFA20,20C,15mm. ff 0 F O >+F OH N F \ phenylephrine CH3

2‘ 803*Py1‘; pyridine OH 90cc, 130mm

F

NOF 0 F OH 0 HF 3. aq. 1M KHco3 NHCH3 N\ F 25 0C,0vernighl CH3 0 /O K 28% \s // Q(3 phenylephrine 3-O-suifate, potassium salt

FIGURE 1 Patent Application Publication Aug. 7, 2014 Sheet 2 0f4 US 2014/0221426 A1

Figure 2A. Inhibition of 4-Methylumbellifer0ne Metabolism .

4-Methylumbelliferone

A

4-Methylumbelliferonemetabolized (as%ofsolutionwithoutcells)

Figure 28. Inhibition of 1-Naphthol Metabolism.

1-Naphthol

1~Naphtholmetabolized (as%ofsolutionwithoutcells) Patent Application Publication Aug. 7, 2014 Sheet 3 of4 US 2014/0221426 A1

Figure 2C. Inhibition of Raspberry Ketone Metabolism.

Rasketone (raspberry ketone) 1

239.mewo~=on§wE x.mi:oréow*0305.?3:00

Figure 2D. Inhibition of Metabolism.

Pinoresinoi w8642

moooéoo Q Patent Application Publication Aug. 7, 2014 Sheet 4 of 4 US 2014/0221426 A1

Figure 2E. inhibition of Magnoiol Metabolism.

Magnolol

80- ~1—

60 Magnololmetabollzed (as%ofsolutionwithoutcells) 40

ii 1* 2

Figure 2F. Inhibition of a-Mangostin Metabolism.

a-Mangostin

A

a-Mangostmmetaboilzed (as%ofsolutionwithoutcells) US 2014/0221426 A1 Aug. 7, 2014

SELECTIVE METABOLIC APPROACH TO inhibiting or reducing the rate of biotransforrnation of drugs INCREASING ORAL BIOAVAILABILITY OF in the liver or intestines. Qazi does not identify the extract as PHENYLEPHRINE AND OTHER PHENOLIC including GRAS compounds. BIOAC TIVITIES [0010] US. Pat. No. 6,180,666 to Wacher et al. describes [0001] Portions of this invention were made using funding orally co-administering a compound of interest with a gallic from the National Institutes of Health (NIH/NCMHD Grant acid ester such as octyl gallate, propyl gallate, lauryl gallate, and methyl gallate. Gallic acid is a trihydroxybenzoic acid, a No. 1P60-MD002256), and the US. Government has certain rights in this invention. type of organic phenolic acid found in plants such as gallnuts, sumac, witch hazel, tea leaves, and oak bark. The gallic acid BACKGROUND ester is purportedly present in order to inhibit biotransforma tions of drugs that are carried out e.g. by cytochromes P450. [0002] 1. Field of the Invention The esters are described as GRAS compounds. [0003] The invention is generally related to increasing the [0011] US. Pat. No. 6,121,234 to Benet et al., describes a bioavailability of bioactive compounds which are adminis method for purportedly increasing bioavailability and reduc tered or taken orally, and more particularly, to using com ing inter- and intra-individual variability of an orally admin pounds which are generally regarded as safe (GRAS), par istered hydrophobic pharmaceutical compound. In Benet, the ticularly certain phenolic compounds, to prevent or decrease pharmaceutical compound is orally co-administered with an pre-systemic or systemic metabolism or clearance of the bio essential oil or essential oil component. Benet suggests that active compounds. the role of the essential oil may be to inhibit drug biotrans [0004] 2. Description of the PriorArt formation in the gut. Essential oils are described as GRAS [0005] Increasing the bioavailablity of compounds pro compounds. vided to a subject to treat various diseases has been a subject [0012] US patent application 2003/0215462 to Wacher et of intense investigation for a number of years. Furthermore, al. describes using UDP-glucuronosyltrasnsferase (UGT) there have been a number of approaches that have employed inhibitors to increase the bioavailability orally administered compositions that include a drug in combination with sub drugs. Wacher suggests the formulation may be used with stances that are Generally Regarded As Safe (GRAS) com 2-methoxyestradiol, , irinotecan, SN-38, , pounds. labetalol, dilevalol, zidovudine (AZT) and morphine. The [0006] US. Pat. No. 5,972,382 to Majeed et al. teaches UDP-inhibitors are generally natural products and include compositions and methods for the improvement of gas epicatechin gallate, , octyl gallate, trointestinal absorption and systemic utilization of nutrients propyl gallate, , tannic acid, benzoin gum, capsai and nutritional supplements by combining them with pip cin, dihydrocapsaicin, eugenol, gallocatechin gallate, erine, an alkaloid derived from black pepper. Maj eed does not geraniol, menthol, menthyl acetate, , allspice berry discuss the delivery of drugs per se, and piperine is not a oil, N-vanillylnonanamide, clovebud oil, peppermint oil, sili GRAS compound. binin, and silymarin. Wacher does not list and [0007] US. Pat. No. 7,576,124 to Harris describes “?rst phenylephrine as exemplary drugs, nor are the GRAS sub pass” inhibiting furocoumarin compounds that are purport stances propyl paraben, vanillin, vitamin C and curcumin edly safe and effective. The furocoumarins are citrus-derived identi?ed as being useful in Wacher. The objective of the substances prepared from, e.g., grapefruit. Harris does not Wacher technology appears to be the identi?cation of speci?c identify which components of pre-systemic metabolism are combinations of drugs and inhibitors that work well together. inhibited, but the cytochrome P450 family of enzymes is Wacher notes that “ . . . a compound that inhibits the glucu referenced. The furocoumarins are not described as GRAS. ronidation of one substrate does not necessarily prevent the [0008] US. Pat. No. 7,125,564 to Chen et al. discusses glucuronidation of all UGT substrates . . . ”. problems associated with ?rst-pass degradation of bioactive [0013] US patent applications 2006/0040875 and 2009/ treatment compounds, and teaches the use of water-soluble 0093467 to Oliver et al. describe UGT2B inhibitors that can complexes with glycyrrhizin, which is the main sweet-tasting increase the bio-availability of drugs. Speci?cally named compounds from licorice root. Glycyrrhizin is described as inhibitors are natural products such as capillarisin, isorham GRAS. Chen does not indicate that glycyrrhizin can inhibit netin, [3-naphtho?avone, (x-naphtho?avone, hesperetin, terpi ?rst pass metabolism; rather, Chen discusses having the com neol, (+)-limonene, [3-myrcene, swertiamarin, eriodictyol, positions parenterally administered to avoid the ?rst-pass cineole, , baicalin, ursolic acid, isovitexin, lauryl effect. alcohol, puerarin, trans-cinnamaldehyde, 3-phenylpropyl [0009] US. Pat. No. 7,070,814 to Qazi et al. teaches com acetate, isoliquritigenin, paeoni?orin, gallic acid, , positions which are purportedly bioenhancing/bioavailabil glycyrrhizin, protocatechuic acid, ethyl myristate, and ity-facilitating. These compositions include an extract and/or umbelliferone. Suggested drugs for which bioavailability can at least one bioactive fraction from the Cuminum cyminum be increased include morphine, naloxone, nalorphine, oxy plant (i.e., the plant from which the spice cumin is derived). morphone, hydromorphone, dihydromorphine, codeine, nal This extract is combined with drugs, nutrients, vitamins, trexone, naltrindole, nalbuphine and buprenorphine. The nutraceuticals, herbal drugs/products, micro nutrients, and focus of Oliver is on the delivery of analgesics. antioxidants, along with pharmaceutically acceptable addi [0014] US patent application 2010/0087493 to Kaivosaari tives/excipients. Similar to the Majeed patent, Qazi discusses et al. teaches a method for increasing bioavailability of a optionally including piperine (or extract/fraction of piper pharrnacologically active agent that undergoes direct N-glu nigrum or piper longum) to purportedly increase the bene? curonidation by UDP-glucuronosyltransferase isoenzyme cial effect of the extract. Qazi is particularly focused on the UGT2B10 by administering an UGT2B10 modulator, e.g. an problem of pre-systemic metabolism of drugs and suggests inhibitor of UGT2B10 (preferably selectively for UGT2B10 that the compositions described in the patent may function by over UGT1A4). The drugs for which bioavailability may be US 2014/0221426 A1 Aug. 7, 2014

increased are described as having a nucleophilic nitrogen enzymes can be achieved, and the drugs or other bioactive atom, including primary, secondary and tertiary aryl- and agents to be provided therewith are not modi?ed (or are alkylamines, sulfonamides and aromatic or aliphatic hetero modi?ed to a lesser extent) and retain their active form upon cyclic compounds having one or more nitrogen atoms as entering systemic circulation. heteroatoms. Nicotine is identi?ed as an example. The inhibi tors are not described in detail, and only Levomedetomidine [0020] In addition, toxicity that may be associated with is provided as an example. high doses of a bioactive compound is reduced by 1) using [0015] WO/2011/026112 describes methods of increase only GRAS compounds and 2) administering a combination bioavailability of a pharmaceutically active agent by using of different GRAS compounds, each of which is used in lesser speci?c inhibitors of a UGT that glucuronidates the pharma amounts than if administered alone. A combination may ceutically active agent. However, in WO/2011/026112, the include compounds from different GRAS categories e. g. vita inhibitors are described as comprising an N-acyl phenylami mins, phenolic ?avoring agents, antioxidants, etc. Examples noalcohol residue and a uridine moiety connected by a spacer. of drugs or bioactives which may be successfully adminis Thus, the use of GRAS compounds does not described in tered in this manner include phenylephrine, albuterol, WO/2011/026112. 2-methoxyestradiol, and (the natural products) silybin, rasp [0016] WO 2010015636 20100211 teaches beta-carbolin berry ketone, pinoresinol, , (x-mangostin, and res derivatives to inhibit UGTs and thereby increase bioavailabil veratrol; however, it will be recognized by those of skill in the ity of drugs such as antibiotics. However, the use of GRAS art that the invention can be practiced with a number of compounds for this purpose is not discussed. different bioactive agents. [0017] Prior to the present invention, there has been little [0021] The 2006 Stop Meth Act resulted in the substitution work on strategies to increase phenylephrine oral bioavail of phenylephrine for pseudophedrin in many high volume ability, and no approaches which target enzymes which target over the counter (OTC) products. Unfortunately, many phenylyephrine metabolism and which avoid enzymes which patients have been unsatis?ed with phenylephrine products, can result in toxicity and adverse effects. and this is likely due to low oral bioavailability. An embodi ment of this invention pertains to a strategy to improve the SUMMARY absorption of phenylephrine using a safe and selective [0018] Phenolic compounds are commonly substrates for approach to inhibit phenylephrine metabolism. Since the vigorous metabolism processes in the body of a subject, or are availability of pseudoephedrine for non-prescription usage has been limited, many cold/?u products have been substi substrates for ef?ux transporters, or can function as substrates for both processes. These phenolic compounds often have tuted with phenylephrine. However, phenylephrine has low rapid pre-systemic and/ or systemic clearance, or insuf?cient oral bioavailability (<38%) and erratic absorption. (Hengst tissue distribution. As a result, metabolism and transport pro mann and Goronzy, 1982; Kanfer et al., 1993; Stockis et al., cesses often limit the medical utility of various phenolic 1995) Phenylephrine is extensively presystemically metabo compounds as pharmacologic agents. An embodiment of the lized by three major metabolic pathways: sulfation (mostly in the gut), oxidative deamination, and glucuronidation, and of invention uses one or more compounds to inhibit enzymes responsible for the rapid pre-systemic metabolism, and thus these sulfation is the major route. (Hengstmann and Goronzy, allows drugs to be absorbed in the body intact. Preferably, the 1982) Due to its low oral bioavailability, an embodiment of compounds are “generally recognized as safe” (“GRAS”) by this invention employs a strategy that increases the bioavail the US Food and Drug Administration (FDA) or are dietary in ability, and thus clinical ef?cacy, of an oral phenylephrine nature. Exemplary compounds can be vitamins and nutrients product. such as ascorbic acid and , phenolic ?avoring agents [0022] The speci?c enzyme isoforms responsible for such as vanillin and eugenol, antioxidants such as propylgal metabolizing phenylephrine in humans have not been clearly late and propylparaben, and dietary polyphenols such as quer established, despite decades of clinical utility. However, one cetin, and combinations thereof. Compounds, and combina may infer its metabolic route from available data. First, the tions of compounds, and particularly phenolic compounds major metabolite of phenylephrine (PE) following an oral useful in the practice of the invention are discussed in more dose is phenylephrine-3-O-sulfate (PE-3S), but when the detail below. drug is given intravenously it is mainly oxidatively deami [0019] One barrier to attaining high systemic levels of a nated. (Hengstmann and Goronzy, 1982) As a result, it is bioactive (e.g., a drug, neutraceutical, or other entity which inferred that the sulfotransferases (SULTs) in the intestinal causes and increase or decrease of an activity of interest in a wall are mainly responsible for phenylephrine sulfation. As a cell) in a recipient is that the body (e. g. the digestive system or phenolic monoamine, PE bears structural similarities with gut) has a number of enzymes which rapidly modify mol compounds such as dopamine, serotonin, and terbutaline ecules prior to their entry into the circulatory system. This which are good substrates for SULT isoform 1A3 pre-systemic metabolism (also known as the “?rst-pass” (SULT1A3). (Paci?ci and Coughtrie, 2005) Furthermore, effect), converts drugs to forms that are biologically less other data show that SULT1A3 protein is more highly active, or even inactive, and/or which generally have low expressed and has higher enzymatic activity in the small bioavailability. Examples of such enzymes include sul intestine compared to the liver, where it is very low or ab sent. fotransferases (SULT’s), glucuronosyltransferases (UGT’s), (Paci?ci and Coughtrie, 2005; Riches et al., 2009) Besides members of the cytochrome P450 (CYP) family, catechol-O catecholamines, SULT1A3 also conjugates many monoam methyltransferase (COMT), and monoamine oxidases ines including serotonin and the [3-adrenergic agonists such as (MAO’s). By administering drugs or agents of interest salbutamol (albuterol) and terbutaline. (Paci?ci and Cought together with one or more GRAS compounds or phenolic rie, 2005) In fact, SULT1A3 has been proposed as the caus compounds or other compounds described herein which are ative factor in the very low oral bioavailability (14:2%) of inhibitors of these metabolic enzymes, inhibition of the terbutaline. (Pearson and Wienkers, 2009) US 2014/0221426 A1 Aug. 7, 2014

[0023] In an embodiment of the invention, one or more substrate selectivity toward phenols. (Paci?ci and Coughtrie, inhibitor compounds (e.g. SULT, UGT, CYP, COMT and/or 2005) Furthermore, SULTlBl is the most highly expressed MAO inhibitors) are combined with a bioactive (e.g., phe isoform in the human intestine, and is capable of sulfating nylephrine). On oral administration of the combination to a thyroid hormones as well as other prototypical SULT sub subject (e.g., human or animal), the one or more inhibitor strates including l-naphthol and p-nitrophenol; beyond this, compounds inhibit the enzymes responsible for the rapid its substrate selectivity is poorly understood. (Riches et al., pre-systemic metabolism, thus allowing the drug to be 2009) SULT2A1 is also expressed in the human intestine and absorbed intact. The inhibitor compounds are preferably cho sulfates phenols. (Riches et al., 2009) Other SULTs are sen from the FDA’s list of GRAS compounds, or the FDA’s expressed at low levels in the intestine and/ or do not accept list of food additives (EAFUS), or other dietary compounds phenols/monoamines as substrates. (Paci?ci and Coughtrie, including dietary supplements. Combinations of inhibitor 2005; Riches et al., 2009) compounds can be used to synergize inhibitory effects while [0029] From the data discussed above, the inventors of the minimizing toxicity of each compound used. Combinations present invention infer that SULTs (including isoforms lAl, of compounds from the same or different categories (includ 1B1, 2A1, and especially 1A3) play an important role in the ing but not limited to vitamins and nutrients such as ascorbic intestinal presystemic metabolism of phenylephrine, and may acid and niacin; phenolic ?avoring agents such as vanillin and play an important role in the intestinal presystemic metabo eugenol; antioxidants such as propylgallate and propylpara lism of a number of other bioactives. The approach for ben; and dietary polyphenols such as quercetin) can be used. increasing the bioavailability of phenylephrine (or other bio [0024] In an exemplary embodiment of the invention, a active) described herein operates on the premise that intesti subject (human or animal) is provided with an oral dose of a nal SULT activity is the major determinant of presystemic bioactive in combination with one or more enzymatic inhibi metabolism of phenylephrine, and that inhibiting intestinal tors (sulfotransferases (SULTs), glucouronosyltransferases SULT results in a signi?cant increase in oral bioavailability of (UGTs), members of the cytochrome P450 (CYP) family, phenylephrine (or other bioactives, e. g., 2-methoxyestrodiol, catechol-o-methyltransferases (COMTs), and monoamine resveratrol, etc.). To increase bioavailability of a bioactive, a oxidases (MAOs)). Exemplary bioactives can include phe suf?cient quantity of one or more SULT inhibitors should be nylephrine, albuterol, 2-methoxyestraodiol, silybin, rasp combined with the bioactive (e. g., PE), so that the when the berry ketone, pinoresinol, magnolol, (x-mangostin, resvera combination is taken orally, a greater amount of the PE trol, raloxifene, estradiol, ethinyl estradiol, terbutaline, remains intact for absorption into the circulatory system than etilephrine, synephrine, octopamine, pterostilbene, if the SULT inhibitors were not included. mangiferin, puerarin, salvianolic acid A, tyrosol, , [0030] An oral dose of PE is substantially glucuronidated to marsupsin, irigenin, caffeic acid phenethyl ester (CAPE), form phenylephrine-3 -O-glucuronide (PE 3G). (Hengstmann nimbidiol, dobutamine, prenalterol, ritodrine, nadolol, labe and Goronzy, 1982) As with the other metabolic pathways, it talol, isoproterenol, L-dopa, methyldopa, salsolinol, horde is not known which isoform of uridine diphosphate glucu nine, rosmarinic acid, ellagic acid, emodin, and amento?a ronosyltransferase (UGT) is most responsible for the glucu vone. In some embodiments the one or more bioactives are ronidation of PE in either the intestine or the liver. However, present in a dose ranging from 0.1 mg to 200 mg, and said one since UGTlAl, 1A6, and 1A9 glucuronidate phenols, sero or more enzymatic inhibitors are present in a dose ranging tonin, and propofol (respectively), (Court, 2005) their activity from 0.25 mg to 225 mg. toward phenylephrine may be inferred. Inhibition of intesti nal and/or hepatic UGTs may help to improve the oral bio DESCRIPTION OF THE DRAWINGS availability of phenylephrine, and this approach may also be [0025] FIG. 1 is a schematic drawing of a synthesis proce effective with other bioactives. In some applications, com dure bining one or more inhibitors of SULTs with one or more [0026] FIGS. 2A-F are graphs showing test results for vari inhibitors of UGTs may be advantageous for increasing the ous compounds incubated with LS180 cells as described bioavailability of bioactives. To increase bioavailability of a above in the absence or presence of inhibitor treatment com bioactive, a suf?cient quantity of one or more SULT inhibi binations A or B (see Example 4) tors and one or more UGT inhibitors shouldbe combined with the bioactive (e.g., PE), so that the when the combination is DETAILED DESCRIPTION taken orally, a greater amount of the PE remains intact for absorption into the circulatory system than if the SULT [0027] SULT1A3 is a major isoform highly expressed in inhibitors and/or UGT inhibitors were not included. the intestine, but poorly expressed (or undetectable) in the [0031] In addition, monoamine oxidase isoforms A and B liver. (Riches et al., 2009) Furthermore, the activity of human (MAO-A and MAO-B) are implicated in the oxidative deami gastrointestinal SULTs has been characterized, and the nation of phenylephrine. (Kanfer et al., 1993) As a result, dopamine sulfation activity (which includes SULT1A3 and phenylephrine is contraindicated in patients taking monoam 1A1) was much higher in the small intestine than the stomach ine oxidase inhibitors, including selegiline, pargyline, and or colon; it was also three-fold higher than the liver. (Chen et clorgyline for various psychiatric and neurological condi al., 2003) These data have been considered and integrated into tions. (Lexi-Comp Online) It is not known whether MAO-A pharmacokinetic models, which assert that intestinal sulfa or MAO-B plays a more important role in phenylephrine tion (particularly mediated by SULT1A3) is the major deter metabolism. However, upon intravenous PE dosing, the minant of pre-systemic metabolism of terbutaline and salb metabolism of PE occurs mainly through oxidative deamina utamol (albuterol). (Mizuma et al., 2005; Mizuma, 2008) tion to form 3-hydroxymandelic acid (3HMA), (Hengstmann [0028] Additionally, SULTlAl is expressed in both the and Goronzy, 1982) suggesting the liver’s role in this path small intestine and the liver, although its expression and activ way. As a result, inhibition of MAO enzymes in the intestine ity are higher in the liver, and it exhibits a more general alone may not signi?cantly improve the oral bioavailability of US 2014/0221426 A1 Aug. 7, 2014

phenylephrine (or other bioactives). Furthermore, inhibition 37° C. for 14 to 17.5 hours, as indicated. The LS180 model of MAO in the intestine and the liver should be avoided to provides an inexpensive method to imitate the human intes minimize the possibility of adverse effects of dietary and tine, with regards to PE metabolism. Unlike animal models or biogenic amines on the nervous system. Therefore, in an recombinant enzymes, this system has the advantages of embodiment of the inventive strategy set forth herein avoids being of human origin (thus avoiding species differences) and compounds with MAO inhibition. However, in some appli including some consideration of the ability of the inhibitors to cations, combining one or more inhibitors of SULTs with one cross the cell membranes and reach the enzymes. For the or more inhibitors of MAOs may be advantageous for increas LS 1 80 experiments, LS 1 80 cells are seeded at the concentra ing the bioavailability of bioactives. To increase bioavailabil tion of 1.9><105 cells/ml in 12-well plate. Cells are incubated ity of a bioactive, a suf?cient quantity of one or more SULT with 0.5 ml DMEM containing 1% non-essential amino acid inhibitors and one or more MAO inhibitors should be com bined with the bioactive (e.g., PE), so that the when the (pH 7.4) with phenylephrine (50 uM)/ inhibitor (100 uM) combination is taken orally, a greater amount of the PE (except ascorbic acid: 1000 uM) for 14 hr to 17.5 hr at 37° C. remains intact for absorption into the circulatory system than with 5% C02. After incubation, medium is removed and if the SULT inhibitors and/or MAO inhibitors were not stored at —800 C. until analysis. The metabolic reactions are included. quenched by placing 12-well plate on ice and quickly rinsing [0032] Interpreting the data published by Hengstmann, the each well. The cell extraction of metabolites is carried out mass balance of total radioactivity excreted into urine follow with 1 ml 2% acetic acid solution in methanol. Cells are ing an oral dose was 92% of what was recovered following an scraped and collected in centrifuge tubes. The suspension is intravenous dose, so that phenylephrine would therefore be mixed for 2-3 min and centrifuged at 18,000 rcf for 5 min. considered a “high permeability” compound. (Hengstmann Supematants (800 [1.1) are collected. After scraping, each well and Goronzy, 1982; Amidon et al., 1995) Combining this with is washed twice as above. The washing solution is collected its high aqueous solubility, phenylephrine would be classi?ed with the supernatant and dried under reduced pressure. The as a Biopharmaceutical Classi?cation System (BCS) class 1 residue is re-suspended in 35 [11 water and analyzed by HPLC. compound. (Amidon et al., 1995) As a BCS class 1 com All the samples are analyzed for PE by HPLC with a phenyl pound, PE disposition is expected mainly to be due to column (150x32 mm, 5 pm, 55° C.) at the ?ow rate of0.75 ml metabolism, and formulation changes which do not affect (20% methanol and 80% (aqueous 1% acetic acid)) and dissolution are not expected to change bioavailability. (Ami detected by ?uorescence (excitation 270 nm, emission 305 don et al., 1995; Wu and Benet, 2005) Therefore, to improve nm). The data are processed with one-way ANOVA followed the oral bioavailability of PE, a metabolism-targeted by Dunnett’s post test; * indicates p<0.05. approach would be most useful. [0033] As a result, a premise of the inventive approach to TABLE 1 improve PE (or other bioactive) bioavailability described herein is to escape the intestinal presystemic metabolism. An Table 1: Extent ofPE (50 nM) Disappearance with Phenolic aspect of the strategy selectively inhibits the enzymes in the Dietary Compounds gut metabolizing PE, without affecting their activity in the liver. In such a way, oral bioavailability of PE would be Extent of PE increased, while adverse drug interactions or systemic toxic Disappearance (as Incubation ity would be avoided. Compound % of control) SD Time (hr) [0034] Preferred inhibitors would have similar solubility propylparaben 53.80% 75.30% 14 compared to PE, and would not exhibit toxicities of their own. propylparaben + ascorbic acid 56.40% 77.90% 14 Furthermore, they would not inhibit the systemic metabolism vanillin 90.20% 42.30% 14 of neurotransmitters (dopamine, norepinephrine, serotonin) propyl gallate 114.30% 48.50% 14 so that adverse effects on the central nervous system and the *curcurnin 24.50% 24.20% 17 cardiovascular system could be avoided. Compounds on the *eugenol + propylparaben + 31.10% 18.80% 17 vanillin + ascorbic acid FDA “generally recognized as safe” (GRAS) list, as well as *propylparaben + vanillin 37.00% 19.40% 17 certain food additives (“everything added to food in the *eugenol + propylparaben 42.60% 14.50% 17 United States,” EAFUS) and dietary supplements (DS), *zingerone 52.40% 25.20% 17 would be likely to be safe, and facilitate regulatory approval. methylparaben 75.90% 24.30% 17 [0035] The inhibitors which can be used in the practice of ethylvanillin 76.50% 19.10% 17 the invention are wide ranging. Tables 1 and 2 show results *resveratrol 14.20% 48.50% 17.5 with a number of different compounds which can function as quercetin 48.70% 16.00% 17.5 *eugenol + vanillin 57.50% 35.70% 17.5 inhibitors of SULT, MAO, CYP, COMT or UGT enzymes, or naringin 75.70% 14.40% 17.5 which otherwise may be used to increase the bioavailability eugenol 133.00% 52.70% 17.5 of the exemplary bioactive phenylephrine. Table 1 shows the *curcurnin + resveratrol 0.00% i 18.5 effect of combinations of phenolic compounds for inhibiting *curcurnin + pterostilbene + 0.00% i 18.5 PE metabolism as indicated by a decrease in PE disappear resveratrol + zingerone ance, and Table 2 shows the same effect as indicated by the *pterostilbene + zingerone 36.50% 12.20% 18.5 loss of PE sulfate formation. In Tables 1 and 2, human LS 1 80 *guaiacol 51.30% 13.90% 18.5 intestinal cells were used for screening the inhibition of PE *pterostilbene + zingerone 41.80% 7.40% 19 metabolism. For the experiment which produced the results in *pterostilbene 70.60% 7.20% 19 Table 1, the concentration of PE was 50M; the concentration *isoeugenol 73.90% 7.50% 19 of vitamin C (where present) was 1 mM; the total concentra tion of other inhibitors was 100 uM. Cells were incubated at US 2014/0221426 A1 Aug. 7, 2014

TABLE 2 [0039] Other ?avonoids which may be used include but are not limited to ?avanols (such as catechin, gallocatechin, epi Inhibition of PE Sulfate Formation with Phenolic Dietary Compounds catechin, catechin gallate, gallocatechin gallate, epigallocat PE Sulfate echin, epicatechin gallate, epigallocatechin gallate, leucoan Formation Incubation thocyanidin, and proanthocyanidins), ?avones (such as Compound (as % of control) SD Time (hr) luteolin, apigenin, tangeretin), ?avonols (such as quercetin, *guaiacol 33.00% 7.34% 18.5 , myricetin, ?setin, isorhamnetin, pachypodol, *curcumin + resveratrol 0.10% i 18.5 rhamnazin), ?avanones (such as hesperetin, hesperidin, eri *pterostilbene + zingerone 28.30% 4.49% 18.5 odictyol, homoeriodictyol), ?avanonols (such as taxifolin, *curcumin + pterostilbene + 0.70% i 18.5 dihydroquercetin, dihydrokaempferol), anthocyanidins (such resveratrol + zingerone as anthocyanidin, cyanidin, delphidin, malvidin, pelargoni din, peonidin, petunidin), iso?avones (such as genistein, [0036] These results in Tables 1 and 2 demonstrate the , glycitein), iso?avanes (such as , lonchocar extent to which exemplary combinations of inhibitors inhibit pane, laxi?orane), and neo?avonoids (such as dalbergin, the metabolism of phenylephrine (PE) in the LS180 intestinal nivetin, coutareagenin, dalbergichromene). Glycosides of the cell culture model. Note that some combination treatments ?avanols, ?avonol, ?avones, ?avanones, ?avanonols, antho were more effective than single agent treatments. While van cyanidins, iso?avones, iso?avanes, and neo?avonoids may illin and eugenol failed to inhibit PE metabolism alone, in also be used. combination together or with other agents they signi?cantly [0040] (such as silybin, silybininA, silybin and synergistically inhibited it. Curcumin and resveratrol B, silydianin, silychristin, isosilychristin, isosilybin A, isosi were more effective in combination(s). lybin B, , silychristin, silydianin, dehydrosilybin, [0037] In connection with the data above, FIG. 1 illustrates deoxysilycistin, deoxysilydianin, silandrin, silybinome, sily an exemplary synthesis route for phenylephrine 3-O-Sulfate. hermin and neosilyhermin, silyamandin, hydnocarpin, Phenylephrine 3-O-sulfate was dissolved in 2 molar equiva scutellaprostin A, B, C, D, E and F; hydnowightin, palstatin, lents of tri?uoroacetic anhydride and incubated at room tem salcolinA and salcolin B, rhodiolin) and their glycosides may perature for 15 minutes to protect the alkyl hydroxyl and the also be used in the practice of the invention. (pinores secondary amine. The product was puri?ed by silica gel chro inol, , , , , sec matography. It was then dissolved in pyridine with 3-4 molar oisolariciresinol, , , syrin equivalents of pyridine-sulfur trioxide complex with heat and garesinol and ) and their glycosides would be stirring. Pyridine was evaporated, followed by hydrolysis in included. Xanthones (alpha-mangostin, beta-mangostin, aqueous potassium bicarbonate at room temperature over gamma-mangostin, garcinone, garcinone A, garcinone C, night, and puri?ed by HILIC-amide chromatography. LC garcinone D, mangostanol, gartanin) and their glycosides MS/ MS (ESI—) reveals a 246>166 mass transition indicating may be used in the practice of the invention. Miscellaneous the loss of S03 from the phenol. This synthesis enables the natural phenolic compounds may also be included such as detection of the main metabolic product of the SULT enzyme hydroxy-methoxy-coumarins, hydroxy-chalcones, biocha activity on phenylephrine, as shown in Table 2. nin A, prunetin, kavalactones (1 1-hydroxyyangonin; 1 1 -methoxy- 1 2-hydroxydehydrokavain; 5-hydroxykavain), [0038] In addition to the compounds and combinations of compounds indicated to have inhibitory capacity, and thus, ellagic acid, rosmarinic acid, emodin, and amento?avone. the capacity to increase the bioavailability of PE (as well as [0041] Furthermore, suitable inhibitory compounds for use other bioactives), other compounds which may be employed in the practice of the invention can be readily identi?ed using to increase the bioavailability of orally provided bioactives enzymatic activity assays. Exemplary assays are set forth may be selected from methyl paraben, ethyl paraben, propyl below: paraben, butyl paraben, (—)-Homoeriodictyol; 2,6-dimethox [0042] SULTs: yphenol; 2-isopropylphenol; 2-methoxy-4-methylphenol; [0043] Selected recombinant SULT isoforms (including 2-methoxy-4-propylphenol; 4-(1 ,1 -dimethylethyl)phenol; 1A1, 1A3, 1B1, 2A1) are available commercially from a 4-allylphenol; 4-ethylguaiacol; 4-ethylphenol; anisyl alco variety of sources including Xenotech. Appropriate control hol; butylated hydroxyanisole; butylated hydroxytoluene; substrates should be used; for example, 4-methylumbellifer carvacrol; carveol; dimethoxybenzene; divanillin; essential one for SULTlAl and 1B1; 1-naphthol for SULT1A3; estra oils+extracts (e.g., clove, cinnamon, nutmeg, rosemary, cit diol for SULT2A1. (Paci?ci and Coughtrie, 2005) Assays rus, vanilla, ginger, guaiac, turmeric, grape seed, black pep should be performed according to the manufacturer’ 5 instruc per, etc.); ethyl p-anisate; eugenyl acetate; eugenyl formate; tions (Cypex/Xenotech LLC). Brie?y, substrates should be isoeugenol (acetate, formate, or benzoate); L-tyrosine; incubated at 37° C. in the presence or absence of 3'-phospho methyl anisate; methylphenyl ether; methylphenyl sul?de; adenosine 5'-phosphosulfate (PAPS; 20 uM) in 50 mM potas O-(ethoxymethyl)phenol; O-cresol; O-propylphenol; resor sium phosphate buffer (pH 7.4) containing 5 mM magnesium cinol; salicylates (amyl, benzyl, butyl, ethyl, methyl, etc.); chloride and 10 mM dithiothreitol. Initial substrate concen thymol; trans-; vanillin propylene glycol acetal; tration should be 2 uM, with a protein concentration of 2.5 vanillyl acetate; vanillyl alcohol; vanillyl ethyl ether; vanil ug/ml, incubating for 5-60 minutes. Reactions should be lylidene acetone; veratraldelhyde; and xylenols (2,6-; 2,5-; stopped with acetonitrile, and analyzed by reversed-phase 3 ,4-). Other herbal/ natural compounds not on GRAS/EAFUS HPLC to determine disappearance of the control substrate list which may be used to increase the bioavailability of orally (and/ or formation of the metabolites), and PE (or other bio provided bioactives include hesperetin; eriodictyonone; 5,3' active) and/or their metabolites should be analyzed. Dihydroxy-7,4'-dimethoxy?avanone; isorhamnetol; tama [0044] UGTs: rixetin; syringetin; 3',7-Dimethquuercetin; and methylated [0045] Selected recombinant UGT isoforms (including and/ or dehydroxylated analogs of quercetin. 1A1, 1A6, 1A9) are commercially available from a variety of US 2014/0221426 A1 Aug. 7, 2014

sources including BD Biosciences. Appropriate control sub bolic syndrome, various cancers, in?ammatory diseases (in strates should be used; for example, estradiol, l-naphthol, and cluding arthritis), and anti-aging (antioxidant) activities. propofol should be used as control substrates for UGTlAl, 1A6, and 1A9, respectively. (Court, 2005) Determinations EXAMPLES should be performed in Tris-HCl buffer (50 mM; pH 7.5) containing magnesium chloride 8 mM, alamethicin 25 ug/ml, Example 1 incubated at 37° C. in the presence or absence of 2 mM uridine 5'-diphospho-glucuronic acid (UDPGA). Initial sub In Vitro Inhibition of Phenylephrine (PE) Sulfation strate concentration should be 1 uM, with a protein concen by Phenolic Dietary Compounds tration of 200 ug/ml, incubating for 5-60 minutes. [0046] rrpr)$ [0051] Background. [0047] Recombinant MAO isoforms (A and B) are com [0052] This in vitro study aimed to investigate the feasibil mercially available from a variety of sources including BD ity of inhibiting the pre-systemic sulfation of PE. Biosciences. Appropriate control substrates should be used; [0053] Methods. for example, kynuramine is a substrate of both isoforms form [0054] Phenolic compounds were selected from FDA’s ing a ?uorescent product by oxidative deamination. (Herraiz “GRAS” list, approved food additives, or dietary supple and Chaparro, 2006) Determinations should be performed in ments. LS180 cells were used as a model to test the effect of 100 mM potassium phosphate buffer (pH 7.4), incubated at these phenolic compounds on the pre-systemic sulfation of 37° C. The initial substrate concentrations should be 1 uM, PE. The cells were incubated in 0.5 ml medium with PE (50 with a protein concentration of 50 ug/ml, incubating for 5-60 uM):inhibitor (100 uM) overnight. Extracellular buffer was minutes. collected and cells were extracted with methanol. PE was [0048] While the data are particularly compelling in terms determined by reversed-phase HPLC with ?uorescence of showing that certain inhibitory compounds or combina detection. The formation of PE-sulfate was analyzed by LC tions of compounds can prevent the metabolism of phenyle MS/MS. Results (n:3 per group) were analyzed by one-way phrine, the invention may be practiced with a variety of other ANOVA with Dunnett’s post-test (p<0.05; Prism 5). bioactives including the following: albuterol, raloxifene, [0055] Results. estradiol, ethinyl estradiol, terbutaline, etilephrine, syneph [0056] The extent of disappearance of PE (con rine, octopamine, resveratrol, pterostilbene, magnolol, trol:503:l27 pmol/hr) was signi?cantly (p<0.05) decreased mangiferin, puerarin, resveratrol, salvianolic acid A, raske to the following (meaniSD, as % of control): curcumin tone (a.k.a. “raspberry ketone”), tyrosol, honokiol, mar 24:24%, guaiacol 5l:l4%, isoeugenol 74:8%, pterostil supsin, irigenin, caffeic acid phenethyl ester (phenylethyl bene 71:7%, resveratrol l4:48%, zingerone 52:25%, and caffeate; “CAPE”), and nimbidiol. the combinations eugenol+propylparaben 43: l 5%, vanillin+ [0049] Clinically, the inhibitors utilized in the practice of propylparaben 37:l9%, eugenol+propylparaben+vanillin+ the invention are preferably acceptable to regulatory bodies ascorbic acid 31:19%, eugenol+vanillin 58:36%, and (such as the FDA) and without adverse effects. For example, pterostilbene+zingerone 37:12%. The combinations of cur the acceptable daily intake of eugenol, ethyl vanillin, and cumin+resveratrol and curcumin+pterostilbene+resveratrol+ vanillin are 2.5, 3.0, and 10 mg/kg/day, respectively (Fen zingerone almost completely inhibited PE disappearance. aroli, 2010). As another example, pterostilbene is FDA Correspondingly, PE-sulfate formation was inhibited by approved as a GRAS compound in dosages of 30 mg/kg/day. guaiacol to 33:7% (control:100%; 6650:260 uV*s) and by Quercetin is a GRAS substance which is also marketed as a pterostilbene+zingerone to 28:4%. The combinations of cur dietary supplement in dosages reaching 500 mg/day, while cumin+resveratrol and curcumin+pterostilbene+resveratrol+ resveratrol and curcumin as dietary supplements are used in zingerone inhibited 299% of PE-sulfate formation. However, doses of 250 mg or 500 mg/ day, respectively. Propylparaben when propyl gallate, vanillin, or eugenol was used alone, they is FDA-approved as an antioxidant/preservative food additive had no signi?cant effect on PE disappearance, suggesting amounting to 0.1% w/w food fat content, thus individual synergy when vanillin or eugenol was used with other com dosages in excess of 10 mg are expected to be permissible. pounds. Doses of each inhibitor is expected to be such that when [0057] Conclusion. dissolved in GI ?uid (250 ml) concentration will be between [0058] Several compounds and combinations including 10-3000 [1M1 minimum dose:2.5 umol (0.25-0.75 mg); resveratrol inhibit the pre-systemic sulfation of PE and can maximum dose:750 umol (75-225 mg), assuming approxi improve its oral bioavailability. mate molecular weights of inhibitors in the range of 100-300 Daltons. Bioactive ingredients would be dosed ranging from 0.5 to 200 mg, depending upon the compound and the thera Example 2 peutic application. [0059] Resveratrol (RES; 25 uM) was incubated with [0050] Many natural phenolic compounds have very low LS180 cells for 4 hours (as described in Example 1) in the oral bioavailability, thus they often fail to result in clinical absence or presence of the inhibitors (100 uM) listed below. bene?ts. This technology would enable the biological activi The compounds marked with asterisks indicate a signi?cant ties of many natural phenolic compounds to be realized by inhibition of resveratrol metabolism (disappearance) com inhibiting their presystemic metabolism thereby improving pared to controls in the absence of the inhibitors. Methylpa their oral bioavailability. Examples of clinical utilities would raben and ethyl vanillin showed the greatest extent of inhibi include diabetes (especially pre-diabetes and type 2 diabe tion of resveratrol metabolism, while cinnamic acid, piperine, tes), heart disease (including hyperlipidemia), liver disease eugenol, vanillin, propylgallate, and propylparaben also (including cholestasis and hepatoprotection), obesity, meta showed signi?cant inhibition. US 2014/0221426 A1 Aug. 7, 2014

TABLE 3 of the compounds, solutions lacking LS180 cells were incu bated under the same conditions and used to correct for the Extent of Resveratrol Disappearance with Phenolic Dietary Compounds. expected concentrations of the compounds in the absence of Extent of RES Disappearance Incubation metabolism. Samples were analyzed by reversed phase Compound (as % of control) SD Time (hr) HPLC with ultraviolet and/ or ?uorescence detection, results were compared by one-way ANOVA with Dunnett’ s post test. *methylparaben 0.4% n/a 4 FIGS. 2A-2F show that LS180 cells were able to metabolize *ethylvanillin 8.1% 377.0% 4 *cinnamic acid 16.3% 63.8% 4 >50% of the compounds in the absence of any inhibitor treat *piperine 26.4% 67.6% 4 ment (controls). The data show that Combination A was the *eugenol 38.3% 25.8% 4 most effective treatment for inhibiting metabolism of 4-me *vanillin 44.8% 16.6% 4 thylumbelliferone, 1-naphthol, pinoresinol, magnolol, and *propyl gallate 51.2% 14.5% 4 *propylparaben 57.8% 20.1% 4 (x-mangostin, while Combination B was the most effective *sinapic acid 86.1% 11.7% 4 for inhibiting metabolism of raspberry ketone. zingerone 83.7% 40.9% 4 [0062] Compounds such as raspberry ketone, pinoresinol, caffeic acid 91.1% 9.3% 4 ferulic acid 100.2% 37.9% 4 magnolol, and (x-mangostin have preclinical biological vanillic acid 102.9% 37.4% 4 activities which would be useful in the treatment or preven tion of diseases such as hyperlipidemia, diabetes, obesity, cancer, and in?ammation. However, these compounds also have very low oral bioavailability due to presystemic metabo Example 3 lism, which masks their clinical utility. Our data show that the [0060] 2-Methoxyestradiol (2-ME; 10 uM) was incubated inhibitor combinations described herein can decrease the with LS180 cells for 4 hours (as described above) in the intestinal metabolism of selected phenolic compounds. These absence or presence of the inhibitors (100 uM) listed below. phenolic natural compounds, when utilized with our inhibitor The compounds marked with asterisks indicate a signi?cant combinations to improve their oral bioavailability, can be inhibition of 2-methoxyestradiol metabolism (disappear used more effectively to achieve a clinical bene?t. ance) compared to controls in the absence of the inhibitors. Signi?cant inhibition of 2ME metabolism was observed with Example 5 eugenol, vanillin, propyl gallate, and propylparaben. [0063] Silybin (20 uM) and albuterol hemisulfate salt (20 uM) were incubated for 15 hours with LSl80 cells as TABLE 4 described in Example 4, in the presence or absence of Com Extent of 2—Methoxyestradiol Disappearance with bination A. Albuterol metabolism was signi?cantly inhibited Phenolic Dietary Compounds by CombinationA (p<0.05). The appearance of an unknown metabolite of silybin was signi?cantly inhibited by Combi Extent of 2—ME Disappearance Incubation nation A (p<0.05). Compound (as % of control) SD Time (hr) *eugenol 21.2% 54.8% 1 REFERENCES *eugenol 33.9% 26.9% 1 *vanillin 39.4% 21.4% 1 [0064] Amidon G L, Lennernas H, ShahV P and Crison J R *propyl gallate 42.8% 24.7% 1 (1 995) A theoretical basis for a biopharmaceutic drug clas *propyl gallate 50.4% 14.1% 1 si?cation: the correlation of in vitro drug product dissolu *vanillin 51.2% 14.5% 1 *propylparaben 51.7% 20.6% 1 tion and in vivo bioavailability. Pharm Res 12:413-420. *propylparaben 57.7% 13.7% 1 [0065] Burdock GA (2005) Fenaroli’ s Handbook of Flavor cinnamaldehyde 87. 6% 13.1% 1 Ingredients. 6th Edition, CRC Press, New York. cinnamaldehyde 93.9% 9.0% 1 *sinapic acid 88.1% 10.4% 1 [0066] Chen G, Zhang D, Jing N, Yin S, Falany C N and caffeic acid 93.3% 10.0% 1 Radominska-PandyaA (2003) Human gastrointestinal sul vanillic acid 99.1% 7.9% 1 fotransferases: identi?cation and distribution. ToxicolAppl gallic acid 101.5% 10.8% 1 Pharmacol 187: 186-197. ferulic acid 101.7% 10.2% 1 [0067] Court M H (2005) Isoform-selective probe sub strates for in vitro studies of human UDP-glucuronosyl transferases. Methods Enzymol 400: 104-1 16. Example 4 [0068] Hengstmann J H and Goronzy J (1982) Pharmaco [0061] Compounds were incubated with LS180 cells as kinetics of 3H-phenylephrine in man. Eur J Clin Pharma described above in the absence or presence of inhibitor treat col 21 :335-341. ment combinations A or B or resveratrol. Combination A [0069] Herraiz T and Chaparro C (2006) Human monoam comprises quercetin 50 uM, ethyl vanillin 25 uM, isoeugenol ine oxidase enzyme inhibition by coffee and beta-carbo 25 uM, and propylparaben 25 uM; Combination B comprises lines norharman and harman isolated from coffee. Life Sci 25 [1M each of resveratrol, curcumin, zingerone, and pteros 78:795-802. tilbene; the 3rd treatment is resveratrol 100 uM. The com [0070] Kanfer I. Dowse R and Vuma V (1993) Pharmaco pounds, their concentrations, and incubation times were kinetics of oral decongestants. Pharmacolherapy 13:116 4-methylumbelliferone (1 uM; 1.5 hrs.; FIG. 2A), 1-naphthol S-128S; discussion 143S-146S. (1 uM, 0.5 hrs; FIG. 2B), raspberry ketone (2.5 uM, 15 hrs.; [0071] Mizuma T (2008) Assessment of presystemic and FIG. 2C), pinoresinol (1 uM, 1.5 hrs.; FIG. 2D), magnolol (1 systemic intestinal availability of orally administered uM, 1.5 hrs.; FIG. 2E), and (x-mangostin (1 uM, 1.5 hrs.; FIG. drugs using in vitro and in vivo data in humans: intestinal 2F). To control for any effects of the inhibitors on the stability sulfation metabolism impacts presystemic availability US 2014/0221426 A1 Aug. 7, 2014

much more than systemic availability of salbutamol, 12. The method of claim 10 Wherein said step of providing SULT1A3 substrate. JPharm Sci 97:5471-5476. includes oral administration of vitamin c. [0072] Mizuma T, Kawashima K, Sakai S, Sakaguchi S and 13. An oral dosage form of phenylephrine, comprising Hayashi M (2005) Differentiation of organ availability by phenylephrine and one or more of curcumin, reserveratrol sequential and simultaneous analyses: intestinal conjuga and caffeic acid phenylethyl ester. tive metabolism impacts on intestinal availability in 14. An oral dosage form of phenylephrine, comprising humans. JPharm Sci 94:571-575. phenylephrine, propyl paraben, and one or more of vanillin [0073] Paci?ci G M and Coughtrie M W (2005) Human and eugenol. Cylosolic Sulfolransferases. CRC Press: Taylor & Francis 15. An oral dosage form of phenylephrine, comprising Group, Boca Raton, Fla. phenylephrine, and one or more of quercetin, ethyl vanillin, [0074] Pearson P G and Wienkers L C (2009) Handbook of isoeugenol, propylparaben, guaiacol, pterostilbene, and Drug Metabolism. Informa Healthcare, NeW York. zingerone. [0075] Riches Z, Stanley E L, Bloomer J C and Coughtrie 16. An oral dosage form of phenylephrine, comprising M W H (2009) Quantitative Evaluation of the Expression phenylephrine, and one or more of eugenol, propylparaben, and Activity of Five Major Sulfotransferases (SULTs) in vanillin, and ascorbic acid. Human Tissues: The SULT “Pie”. Drug Melab Dispos 17. An oral dosage form of phenylephrine, comprising 37:2255-2261. phenylephrine, and a combination of curcumin, pterostil [0076] Stockis A, Deroubaix X, Jeanbaptiste B, Lins R, bene, resveratrol, and zingerone. AllemonA M and Laufen H (1995) Relative bioavailability 18. An oral dosage form of phenylephrine comprising phe of carbinoxamine and phenylephrine from a retard capsule nylephrine, pterostilbene and zingerone. after single and repeated dose administration in healthy 19. A method of orally providing a bioactive to a subject in subjects. Arzneimillelforschung 45: 1009-1012. need thereof so as to enhance bioavailiability of said bioac [0077] Wu C Y and Benet L Z (2005) Predicting drug tive, comprising the step of orally providing to said subject disposition via application of BCS: transport/absorption/ With said bioactive in combination With one or more inhibi elimination interplay and development of a biopharmaceu tors selected from the group consisting of sulfotransferases tics drug disposition classi?cation system. Pharm Res (SULTs), glucouronosyltransferases (UGTs), members of the 22:1 1-23. cytochrome P450 (CYP) family, catechol-o-methyltrans 1. A method of orally providing a bioactive to a subject in ferases (COMTs), and monoamine oxidases (MAOs). need thereof so as to enhance bioavailiability of said bioac 20. The method of claim 19 Wherein said bioactives are tive, comprising the step of orally providing to said subject selected from the group consisting of phenylephrine, With said bioactive in combination With one or more inhibi albuterol, 2-methoxyestraodiol, silybin, raspberry ketone, tors of one or more sulfotransferase (SULTs). pinoresinol, magnolol, (x-mangostin, resveratrol, raloxifene, 2. The method of claim 1 further comprising providing said estradiol, ethinyl estradiol, terbutaline, etilephrine, syneph subject With one or more inhibitors of monoamine oxidases rine, octopamine, pterostilbene, mangiferin, puerarin, salvi (MAOs). anolic acid A, tyrosol, honokiol, marsupsin, irigenin, caffeic 3. The method of claim 1 further comprising providing said acid phenethyl ester (CAPE), nimbidiol, curcumin, pterostil subject With one or more inhibitors of uridine diphosphate bene, resveratrol, and zingerone, and combinations thereof. glucoronysl transferases (UGTs). 21. An oral dosage composition, comprising: 4. The method of claim 1 Wherein said bioactive is phe one or more bioactives selected from the group consisting nylephrine. of phenylephrine, pinoresinol, magnolol, rasketone, 5. The method of claim 2 Wherein said bioactive is phe (x-mangostin, silybin, albuterol, resveratrol, 2-methox nylephrine. yestradiol; and 6. The method of claim 3 Wherein said bioactive is phe one or more enzymatic inhibitors selected from the group nylephrine. consisting of quercetin, vanillin, ethyl vanillin, eugenol, 7. The method of claim 1 Wherein said one or more inhibi isoeugenol, methylparaben, propylparaben, propyl gal tors of SULTs inhibits SULT 1A3. late, naringin, ascorbic acid, pterostilbene, resveratrol, 8. A method of orally providing phenylephrine to a subject zingerone, guaiacol, piperine, curcumin, and caffeic in need thereof Which enhances bioavailability of phenyleph acid phenylethyl ester (CAPE). rine, comprising the step of providing, for oral administra 22. An oral dosage composition Wherein said enzymatic tion, phenylephrine to said subject in combination With one or inhibitors include a combination of quercetin, ethyl vanillin, more phenols or alkylated chatecols. isoeugenol, and propylparaben. 9. The method of claim 8 Wherein said phenols or alkylated chatecols are selected from guaiacol, isoeugenol, eugenol, 23. An oral dosage composition Wherein said enzymatic zingerone, vanillin, ethyl vanillin, curcumin, and piperine. inhibitors include a combination of resveratrol, curcumin, 10. The method of claim 9 Wherein said step of providing zingerone, and pterostilbene. includes oral administration of one or more phenolic com 24. An oral dosage composition as claimed in claim 21, pounds Which are not alkylated chatecols. Wherein said one or more bioactives are present in a dose 11. The method of claim 10 Wherein said one or more ranging from 0.1 mg to 200 mg, and said one or more enzy phenolic compounds include trans-resveratrol, trans-pteros matic inhibitors are present in a dose ranging from 0.25 mg to tilbene, propyl paraben, methyl paraben, quercetin, and caf 225 mg. feic acid phenylether ester.