Curcuminoid Drug Interactions

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Peer-reviewed | Manuscript received: May 17, 2015 | Revision accepted: August 17, 2015 Curcuminoid drug interactions

Alexa Kocher, Christina Schiborr, Jan Frank, Stuttgart

Introduction Summary Curcuminoids are lipiphilic secondary The secondary plant metabolite curcumin and the related curcuminoids may be plant metabolites isolated from the valuable in the prevention and treatment of many different degenerative disea- roots of the plant Curcuma longa ses. As curcuminoids are often taken as supplements by some population groups, (turmeric) ( see Schiborr et al., it may be asked whether this can lead to changes in the pharmacokinetics or phar- page M636 [1]) and consist of ca. 77 % macodynamics of other drugs taken at the same time. It is particularly important curcumin, 17 % demethoxycurcumin to clarify this issue, as native curcumin only exhibits low bioavailability, but many and 6 % bis-demethoxycurcumin [2]. novel formulations are being developed that enhance its absorption in the small Because of their many health suppor- intestine and thus lead to higher concentrations of the active drug. Cell culture ting activities, they have long been and animal studies have shown that native curcumin can affect xenobiotic meta- used in traditional Chinese medicine bolizing enzymes. There are also effects on the pharmacokinetics of active sub- for the treatment of respiratory di- stances in animal studies and in men. On the other hand, it has not been shown sease, anorexia, diabetic wounds or that curcumin has any adverse effects on the pharmacological activity of other for digestive disorders [3]. Curcumin drugs. However, it must be emphasized that these studies are preliminary rather supplements are freely commercially than conclusive and must be supported by larger scale investigations. It has also available, mostly as capsules or tab- not been investigated whether the formulations with better bioavailability can lets; many people take them to im- influence the pharmacokinetics of other drugs. prove their health. Keywords: curcumin, curcuminoids, turmeric, drug interactions, safety, drug The oral bioavailability of curcumin is low, i.e. it is poorly absorbed, and rapidly metabolized and eliminated. For this reason, curcumin formulations with better bioavailability are being sold increasingly often; these give much higher plasma concentra- Older and chronically ill people often attempt to improve their health tions of curcumin than native curcumin [1]. by taking food supplements. Thus they often take drugs together with People who take curcumin supple- plant extracts that might influence the effects of these drugs. In the ments are often older or chronically present article, we describe the evidence for drug interactions involving ill and have to take medicines every the secondary plant metabolite curcumin and the related curcumioids. day. This article therefore examines

Citation: Explanation of terms used: Kocher A, Schiborr C, Frank J (2015) Curcuminoid drug inter- An active substance or drug is the substance in a medicine which actions. Ernahrungs Umschau mediates or causes the active effect. The medicine may also contain one or several additional substances (“excipients”) for different for- 62(11): 188–195 mulations (e.g. tablet or syrups). The preparation of different drug This article is available online: formulations is known as pharmacy and can have a major influence DOI: 10.4455/eu.2015.037 on drug activity.

188 Ernaehrungs Umschau international | 11/2015 whether there is published scientif- is often described by the following availability. Because of incomplete ic evidence for interactions between parameters: absorption and metabolism, an curcuminoids – primarily curcumin • physiological half-time of elimina- orally or enterally administered drug

– and medicines (or their active sub- tion (t1/2), has a bioavailability of < 100 %. stances) which may modify their ac- • time to reach the maximum tivity. The focus is on the pharmaco- plasma concentration (tmax), kinetics of various drugs. The effects • maximal plasma concentration The so-called “therapeutic index” of curcumin on drug pharmacodyna- (Cmax) and is an important parameter in asses- mics are mentioned in passing. • area under the concentration time sing the safety of a drug. This is the curve (“area under the curve”, interval between the minimal active AUC) (• Figure 1). and minimal toxic concentration of Key terms the drug [5]. The physiological half-time of eli- Food-drug interaction mination (t1/2) is the time needed for We will use the term “food-drug in- the (plasma) concentration of the ac- Pharmacodynamics (= what the ac- teraction” for changes in the phar- tive substance to sink to 50 % of the tive substance does to the organism) macokinetics or pharmacodynamics initial value. The rate of absorption signifi es the biological activity of an of a drug caused by the uptake of a of a substance can be estimated from active substance [6].

food component [4]. the time (tmax) to reach the max-

imum plasma concentration (Cmax). Food-drug interactions can lead to The area under the concentration time changes in pharmacokinetics and/ The term “pharmacokinetics” (= curve (“area under the curve”, AUC) or pharmacodynamics and modify what the organism does to the ac- refl ects the subject‘s exposure to the the activity and safety profi le of the tive substance) means the sum of drug or nutrient. medicine (side effects = adverse drug all processes to which the active The “bioavailability” describes the reactions) in this way. Thus, a re- substance is subject in the body proportion of a drug or nutrient that duction in the bioavailability of a and includes its absorption, distri- is available to systemic circulation in drug can lead to treatment failure. bution, metabolism and excretion. the body. Intravenous administra- On the other hand, enhanced bio- The kinetic profi le of a substance tion is defi ned as giving 100 % bioavailability can lead to enhanced ac-

Maximal plasma Side effects (plasma

concentration (Cmax) concentration too high)

Therapeutic index Substanz X Treatment failure Substance X [nmol/L Plasma] (plasma concentration too low) [mmol/l plasma]

Time of maximal plasma Time [h] concentration (tmax)

Fig. 1: Typical plasma concentration time curve for a drug

The pharmacokinetics of a substance can be determined by measuring the maximal concentration (Cmax), the time to reach the max-

imal concentration (tmax), and the “area under the curve” (AUC), which refl ects individual exposure to a substance. The therapeutic index describes the concentration range in which the drug is therapeutically active and lies between the minimal effective and the minimal toxic concentrations of the active substance.

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tivity and also possibly to enhanced enzymes. Incubation of human absorption and transport proces- drug toxicity (• Figure 1) [4]. These liver cell microsomes with a cur- ses and metabolism [10]. The op- interactions can be split into various cuminoid extract led to 50 % in- posite effect was observed in a categories: hibition of different CYP450s at rat model. In this study, the ani- (1) Inactivation of the drug ex vivo, the following concentrations: mals were fed for 2 weeks with i.e. outside the body, CYP2C19, 7.4 μmol/L; CYP2B6, 1 % curcumin per kg feed and then (2) Interactions which modify 9.4 μmol/L; CYP2C9, 13.5 the microsomes were isolated from presystemic transport (absorp- μmol/L; CYP3A, 25.3 μmol/L. the intestine and liver. The UGT tion), CYP2D6, CYP1A2 and CYP2E1 activity increased 5.4-, 6.7- and (3) Interactions which modify syste- were only very weakly inhibited 7.2-fold in the proximal, middle mic metabolism and drug elimi- [10]. On the other hand, another and distal sections of the small in- nation, and in vitro study with microsomes testine, respectively. In comparison (4) Interactions which directly influ- found that CYP3A4 and 2D6 were to the control, there was a 3.1-fold ence drug activity (pharmacody- not inhibited by up to 58.3 μmol/L increase in the large intestine and a namics), e.g. by binding to tar- curcumin, while 58.3 μmol/L cur- 1.5-fold increase in the liver [13]. get structures such as receptors. cumin inhibited CYP2C9 and 2C8 by 10.5 % and 22.5 %, respectively [11]. The effects of curcumin Effect of curcumin on mem- Effect of curcuminoids on can also be tissue-specific. After brane transporters enzymes that metabolize feeding rats for 4 days with cur- As the present article cannot pursue foreign compounds cumin (60 mg/kg body weight all interactions between curcumin [BW]), there was a 42 % reduction and membrane transport proteins, The following cell culture and ani- in the intestinal content of CYP3A the discussion will be restricted to mal studies examined the influence protein, but a 91 % increase in the multidrug resistance protein 1 of curcumin on enzymes that me- liver content of this protein [12]. (MDR1; also known as P-glycopro- tabolize foreign compounds. These tein [P-Gp]). MDR1 is a transport studies provide preliminary evidence protein in the plasma membrane and Influence of curcumin on phase that curcumin might influence drug is mainly expressed in the liver, kid- II metabolisms metabolism. neys, gastrointestinal tract and the Curcumin can also affect phase II blood-brain barrier. In the liver, it is enzymes. Thus 12.1 μmol/L and 5.2 expressed on the canalicular apical Modulation of phase I μmol/L of a curcuminoid extract lead side of the membrane (towards the metabolism by curcumin to 50 % inhibition of UGT and SULT lumen), in the intestine on the apical Microsomes are membrane frag- activity, respectively, in colon adeno- membrane of the mucosal cells and in ments of the endoplasmic reticu- carcinoma cells (LS180 cells), an the kidney on the brush border mem- lum that contain active CYP450 intestinal cell model to examine brane of the proximal tubulus cells.

Metabolism of foreign compounds Enzymes metabolizing foreign compounds play a central role in the metabolism, elimination and/or detoxification of foreign compounds (xenobiotics) and thus protect the body from potentially damaging substances. The metabolism of foreign compounds is subdivided into different phases [7].

In phase I (functionalization), enzymes introduce reactive functional groups (e.g. OH, NH2, SH, COOH) into the initial substance, in order to prepare it for phase II reactions (conjugation). The most important class of phase I enzymes are cytochrome P450 mixed function monooxygenases (CYP), which transfer an oxygen atom; these are mainly expressed in the gastrointestinal tract, the lungs and the liver. Isoenzyme CYP3A4 is of particular importance, as it is responsible for the metabolism of 50–60 % of currently marked drugs [8]. Phase II enzymes catalyze conjugation reactions with water soluble groups (glucuronic acid, sulfate, methyl groups, amino groups, glutathione). This enhances the water solubility of the starting substance and facilitates its elimination in bile or urine. The most important phase II enzymes are as follows: UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), N-acetyltransferases (NAT), glutathione-S-transferases (GST), methyltransferases (TPMT) and catechol-O-methyltransferases (COMT). UGT1 and UGT2 are responsible for the glucuronidation of 35 % of drugs that are metabolized by phase II enzymes [7, 9]. The transport of foreign compounds or their phase I and II metabolites out of the cell is designated as phase III. Transport proteins, such as multidrug resistance-related proteins (MRP) and organic anion transporter 2 (OATP2) are expressed in the cell membranes of many tissues, particularly in the liver, intestine, kidney and brain. There they form a protective barrier, to prevent the penetration of foreign substances (including drugs) and play a decisive role in the absorption, distribution and excretion of drugs [7].

190 Ernaehrungs Umschau international | 11/2015 MDR1 acts there as efflux pump and Cmax of a drug (or its metaboli- Drug Area of use/Indica- Literature transports endogenous metabolites, tes) – and thus the quantity of tion exogenous substrates and toxins in drug in the body – are changed Celiprolol Antihypertensive [12] an energy-dependent manner against if curcumin is take at the same the concentration gradient out of the time. • Table 1 gives an over- Clopidogrel Anticoagulant [19] cell and into the bile, intestinal space view of the drugs considered. Diclofenac Analgesic, Anti-inflam- [23] (feces) or urine, so that the drug is • Tables 2 and 3 summarize the matory eliminated from the organism [14]. If results of the individual studies. Everolimus Immune suppressant [18] membrane transporters are inhibited Before the individual studies are Glibenclamid Oral Antidiabetic [22] or induced, this can lead to changes considered, it should be empha- Midazolam Sedative [12] in the systemic or local concentrations sized that only a few studies of active substances [15]. have been performed that had NSAID (non-steroidal an- Antirheumatic [24] In an in vitro study, intestinal cells the primary role of investiga- ti-inflammatory drugs) (LS180) were incubated for 48 h with ting the effect of curcumin on Losartan Antihypertensive [17] 1 or 10 μmol/L curcumin. It was drug pharmacokinetics. Talinolol Antihypertensive [21] found that curcumin increased the Warfarin Anticoagulant [19] activity of the available MDR1, but Animal studies not expression of MDR1 mRNA i.e. Tab. 1: Drugs considered in this review, see too formation of new MDR1 [16]. How- Rats were given 60 mg cur- • Tables 2 and 3 ever, this enhanced the efflux of drugs cumin per kg BW for 4 days from the cell. In another study, rats and on day 5 curcumin plus AUC and Cmax of everolimus (an were administered 60 mg curcumin 30 mg/kg celiprolol (an antihy- immune suppressive and substrate per kg BW by gavage for 4 days. Ex- pertensive and substrate for MDR1). of MDR1 and CYP3A4), and this pression of MDR1 protein in the small In comparison to controls, the AUC could lead to a decrease in drug intestine was reduced by 49 % and in was increased 1.6-fold and Cmax 1.9- activity. In subsequent cell culture the liver increased by 144 % relative to fold. This allows the conclusion that studies, it was shown that curcu- the control group [12]. curcumin inhibits MDR1. In the min inhibits MDR1 and CYP3A4. These studies show that curcumin can same model, a significant increase in However, curcumin metabolites influence phase I and phase II studies, AUC was found for midazolam (a (curcumin glucuronide and sul- as well as the transporter MDR1 in sedative and CYP3A4 substrate), but fate), which are present in blood at both in vitro experiments and in animal not for MDR1, without any effect on higher concentrations than curcu- studies. Curcumin can therefore po- Cmax. This indicates that curcumin min, activate CYP3A4. Thus in this tentially change drug metabolism. As, can inhibit CYP3A4. If curcumin was study, curcumin metabolites had a however, there are differences within only given on day 5 together with one greater effect on everolimus meta- the study results, as well as tissue-spe- of the drugs, there was no change in bolism than did curcumin [18]. cific differences, no general conclusion the pharmacokinetics in comparison In another study, rats were given can be drawn as to whether curcumin to the control [12]. Thus curcumin 25, 50 or 100 mg/kg curcumin for can induce or inhibit drug metabolism. could increase the residence time in 7 days. After receiving curcumin These studies only provide initial evi- blood of the drugs celiprolol and mi- on day 7, the rats were given one dence that curcumin can potentially dazolam, and thus enhance their ac- of the two anticoagulants warfa- influence drug metabolism, or about tivity or the risk of side effects. How- rin (0.2 mg/kg BW) or clopido- the underlying molecular mecha- ever, this only applies if curcumin is grel (30 mg/kg BW). For both nisms. Reliable conclusions about the taken for several days. these drugs, the AUC and Cmax interactions between curcumin and Increases in AUC and Cmax were were significantly enhanced in the drugs can only be made on the basis of also found in another study with rats given 100 mg/kg curcumin. well-planned animal or human studies the antihypertensive losartan. However, there was no change in that specifically examine the effect of Rats were given 100 mg curcumin drug activity. The higher drug con- curcumin on drug pharmacokinetics. per kg BW for 7 days; on day 7, centrations might nevertheless en- they were also given 10 mg/kg hance side effects [19].

losartan. The AUC and Cmax of the Influence of curcumin on losartan metabolite EXP3174 were drug pharmacokinetics also clearly increased [17]. It was Animal studies can provide initial also shown in a rat study that a evidence for drug interactions, but Pharmacokinetic studies can provide single dose of 50 or 100 mg/kg do not accurately reflect foreign evidence whether the AUC, tmax or curcumin significantly reduced the substance metabolism in man, as

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the activities and expression of the of curcumin than native curcumin 95TM, n = 16), 20 mg of the an- different enzymes and transporters does. In order to assess the safety of tidepressive fluoxetine (n = 17) or a may differ between animals and these preparations, we also covered combination of curcumin and fluo- man [20]. studies of synergism between these xetine (n = 18) for a period of 6 formulations and other drugs. Such weeks. In all three groups, there was studies only provide preliminary a non-significant improvement in Human studies evidence and would have to be sup- depression and to the same extent. ported by well-planned pharmaco- There was thus no evidence that The antihypertensive drug talinolol kinetic investigations. curcumin either enhanced or im- (50 mg) was administered together In one study, 45 patients with rheu- paired the activity of fluoxetine [25]. with 300 mg curcumin per day to matoid arthritis (chronic inflamma- Thus, the current evidence indi- 12 healthy volunteers. On day 7, tion of the joints) were administered cates that curcumin in formulations there were significant reductions in for 8 weeks either 50 mg diclofenac, with increased bioavailability does

AUC and Cmax for talinolol in com- an analgesic and anti-inflammatory, not impair the activity of the other parison to the control without cur- or 500 mg curcumin, as the formu- drugs. However, the available stu- cumin [21]. This reduction in the lation BCM-95TM, or both. BCM- dies do not allow any statement to concentration of talinol could theo- 95TM contains not only curcumin, be made about the safety of the cur- retically lead to reduced drug activ- but also curcuma oils to enhance its cumin formulations with increased ity. However, there have been no bioavailability. At the beginning and bioavailability in combination with studies that have detected changes end of the study, the current state of other drugs. in pharmacodynamics when talino- the disease and its progression were lol and curcumin are administered documented with the Disease Activ- together. ity Score (DAS) and pain sensitivity In another study, with type 2 di- and joint swelling were documented Conclusion and outlook abetics (n = 8), it was shown that in accordance with the criteria of the In vitro and in vivo studies show that the oral bioavailability of the com- American College of Rheumatology curcumin can influence transporters mon oral antidiabetic glibenclamide (ACR). DAS and ACR significantly and enzymes that metabolize for- was slightly increased after simul- improved in all three groups. No eign compounds, and can also mo- taneous intake of curcumin. It was synergy was observed between cur- dify drug pharmacokinetics. How- also shown that 11-day intake of cumin and diclofenac, although cur- ever, there are some limitations to curcumin and glibenclamide led to cumin did not decrease the activity the studies described here. Thus, the significantly lower values for blood of curcumin [23]. in vitro and animal studies do not glucose concentrations (fasting In another study, patients with os- allow any reliable conclusion about and postprandial), LDL cholesterol, teoarthritis were given the best pos- the use of curcumin formulations VLDL cholesterol and triacylglycer- sible standard therapy for 8 months in man, as there are often non-spe- ides (fasting), as well as an increase with non-steroidal anti-inflam- cific effects in vitro and curcumin in HDL cholesterol, in comparison to matory drugs, with or without concentrations may be used that glibenclamide treatment alone. This additional curcumin (200 mg/day), can never be reached in vivo. Animal study did show that curcumin has in the form of Meriva, a formula- models are of limited relevance, as favorable effects on the treatment of tion with enhanced bioavailability metabolism of foreign compounds is type 2 diabetes mellitus. However, (see [1]). It was found that addi- not identical in animals and in man. there were only 8 participants, so tional curcumin improved clinical Moreover, the studies also dif- the results must be regarded criti- parameters such as pain, stiffness fer with respect to the purity or cally until they have been confirmed and quality of life and reduced the curcuminoid composition of the in a larger study [22]. levels of the inflammation markers test substances or formulation, interleukins 1 and 6. In the group which makes direct comparison treated with curcumin, there were more difficult. Plant extracts are Other studies reductions in the intake of NSAID normally mixtures of many dif- One limitation of these studies is (–63 %) and of other analgesics ferent substances and this makes that only native curcumin was (-43 %), so that there may be syn- it difficult or impossible to assign examined, not the formulations ergy between curcumin and NSAID the observed affects to a specific with better bioavailability. There is in this population [24]. substance. In addition, few studies a greater risk of drug interactions Another study was performed on in man have been performed that with these formulations, as they patients with depression. These were specifically investigate the effect of give greater plasma concentrations given either 1 g curcumin (BCM- curcumin on drug pharmacoki-

192 Ernaehrungs Umschau international | 11/2015 Species Curcumin Drug Intervention AUC [ng/mL x h]** Cmax [ng/mL] tmax [h] Conclusion Lite- dose (mg/ rature kg body weight [BW]) Drug Drug + Cur- Drug alone Drug + Cur- Drug Drug + Cur- alone cumin cumin alone cumin 60 Celiprolol 5 days curcumin; 2 140.0 3 440.3 492.7 ± 33.2 960.1 2.0 ± 0.0 2.0 ± 0.0 Curcumin significantly (30 mg/kg on day 5, the ± 187.9 ± 210.5* ± 93.4* increased the AUC and

BW) drug was admi- (0–8 h) (0–8 h) Cmax of celiprolol. nistered 30 min after ingestion of curcumin. 60 Midazolam 255.1 657.0 123.2 ± 14.8 259.2 0.5 ± 0.1 0.5 ± 0,1 Curcumin significantly (20 mg/kg ± 27.4 ± 135.6* ± 38.7 increased the AUC of BW) (0–4 h) (0–4 h) midazolam.

Sprague 60 Celiprolol Curcumin was 2 140.0 2 347.63 492.7 ± 33.2 458.2 2.0 ± 0.0 1.8 ± 0.1 Simultaneous admi- Dawley (30 mg/kg administered ± 187.9 ± 287.8 ± 78.0 nistration of curcumin [11] rats BW) simultaneously (0–8 h) (0–8 h) without pretreatment with the drug. with curcumin did not affect the pharmacokinetics of celiprolol. 60 Midazolam 255.1 470.0 123.2 ± 14.8 239.7 0.5 ± 0.1 0.5 ± 0.1 The pharmacokinetics (20 mg/kg ± 27.4 ± 88.4 ± 46.8 of midazolam were not BW) (0–4 h) (0–4 h) influenced by simultaneous administration with curcumin without pretreatment with curcumin. 100 Losartan (10 7 days curcumin, 2 080 3 460 457 ± 63.1 1660 ± 892* 0.4 ± 0.1 0.4 ± 0.1 Curcumin significantly

mg/kg BW) on day 7, the ± 837 ± 1 350 increased the Cmax of drug was admi- (0–12 h) (0–12 h) losartan. nistered 30 min after curcumin Wistar rats dosage. [17] Metabolite 766 1 460 108 ± 61.1 341 ± 187* 3.3 ± 2.3 1.9 ± 0.6 Curcumin significantly EXP3174 ± 416 ± 818* increased the AUC and

(measured, (0–12 h) (0–12 h) Cmax of the metabolite but not ad- EXP3174. ministered) 50 Everolimus Curcumin was 98 262 28 908 6.0 ± 1.8 1.4 ± 0.9* - - Both high and lower (0.5 mg/kg administered at ± 15 408 ± 19 668* doses of curcumin Sprague BW) the same time as (0–9 h) (0–9 h) significantly increased Dawley the drug. the AUC and Cmax of [18] everolimus. rats 100 Everolimus 98 262 ± 27 960 6.0 ± 1.8 1.4 ± 1.2* - - (0.5 mg/kg 15 408 ± 19 812* BW) (0–9 h) (0–9 h) 25 Warfarin 7 days curcumin, 16 680 21 930 1 140 ± 330 1 490 ± 380 3.2 ± 4.3 1.3 ± 0.3 The highest dose of (0.2 mg/kg on day 7, the ± 6 900 ± 11 070 curcumin increased the

BW) drug was admi- (0–∞) (0–∞) AUC and Cmax of war- nistered 30 min farin and clopidogrel. after curcumin However, there was no dosage. change in the pharmacodynamics. 50 Warfarin 16 680 16 340 1 140 ± 330 1 150 ± 290 3.2 ± 4.3 1.7 ± 1.3 (0.2 mg/kg ± 6 900 ± 5 330 BW) (0–∞) (0–∞) 100 Warfarin 16 680 26 640 1 140 ± 330 1 710 3.2 ± 4.3 2.7 ± 2.6 Wistar rats (0.2 mg/kg ± 6 900 ± 5 840* ± 530* [22] BW) (0–∞) (0–∞) 25 Clopidogrel 142 100 144 520 17 940 15 410 1.4 ± 0.6 1.0 ± 0.0 (30 mg/kg ± 64 540 ± 16 410 ± 6 840 ± 3 100 BW) (0–∞) (0–∞) 50 Clopidogrel 142 100 129 380 17 940 18 460 1.4 ± 0.6 1.0 ± 0.6 (30 mg/kg ± 64 540 ± 40 170 ± 6 840 ± 6 360 BW) (0–∞) (0–∞) 100 Clopidogrel 142 100 228 940 17 940 32 610 1.4 ± 0.6 1.13 ± 0.5 (30 mg/kg ± 64 540 ± 71 790 * ± 6 840 ± 9 180 * BW) (0–∞) (0–∞)

Tab. 2: Influence of curcumin on the pharmacokinetics of drugs in animal models * p < 0.05, significantly different from control (drug without curcumin) ** Hours given after AUC signify the period for which the AUC was calculated. AUC: area under the curve; Cmax: maximum plasma concentration; tmax: time to reach the maximum plasma concentration

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Study par- Curcumin Drug Intervention AUC [ng/mL x h] Cmax [ng/mL] tmax [h] Conclusion Litera- ticipants dose [mg] ture Drug Drug + Drug alone Drug + Drug Drug + alone Curcumin Curcumin alone Curcumin 7 days curcumin, on day 7, 12 1 763.7 Curcumin reduced Talinolol curcumin was 1 192.1 ± 106.4 ± healthy 300 ± 377.5 147.8 ± 63.8 2.0 ± 0.7 1.9 ± 0.7 the AUC and Cmax of [19] (50 mg) administered 309.7* 39.9* (0–60 h) talinolol. men simultaneously to the drug. Curcumin tended to increase the AUC and

Cmax of glibenclamide 8 Type- Curcumin and 1 728 000 1 792 000 and led to significantly Glibencla- 321 100 327 800 2-dia- 475 drug were taken ± 68 750 ± 50 930 2.6 ± 0.3 2.4 ± 0.3 lower blood lipid con- [21] mid (5 mg) ± 11 680 ± 6 850 betics for 11 days. (0–12 h) (0–12 h) centrations and blood glucose concentrations than with glibenclamide alone.

Tab. 3: Influence of curcumin on the pharmacokinetics of drugs in human studies AUC: area under the curve; Cmax: maximal plasma concentration; tmax: time to reach the maximal plasma concentration

netics, and the number of partic- 1 ipants is generally too low. Dr. Alexa Kocher Dr. Christina Schiborr Thus, even though none of the cited Prof. Dr. Jan Frank studies detected adverse interactions Universität Hohenheim after curcumin intake, caution is Institut für Biologische Chemie und appropriate when curcumin is ad- Ernährungswissenschaft ministered together with drugs. This Biofunktionalität und Sicherheit der Lebensmittel (140b) must be discussed with the respon- Garbenstr. 28, 70599 Stuttgart sible physician until reliable data are 1 E-Mail: [email protected] available. This would require large human studies to investigate how the pharmacokinetics and pharmacodynamics of drugs are influenced Conflict of Interest by curcumin and its formulations The authors declare no conflict of interest with enhanced bioavailability. according to the guidelines of the International Committee of Medical Journal Editors. It should also be pointed out that older people often take more than one drug. This multimedication can lead to complex interactions between curcumin and these drugs, or between different drugs. Therefore future studies should also investigate how curcumin influences the pharmacokinetics and pharmacodynamics of drugs which are taken simultaneously. Additional attention should also be paid in cell culture, animal and human studies to the biological activity of curcumin metabolites (phase II metabolites), as these are present in circulation at much higher concentrations than the parent compound.

194 Ernaehrungs Umschau international | 11/2015 References

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