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Drug Interactions in the Multidrug Therapy of HIV Infection Alice K

Drug Interactions in the Multidrug Therapy of HIV Infection Alice K

Polypharmacy Problems: Drug In the Multidrug Therapy of HIV Infection Alice K. Pau, Pharm.D Clinical Pharmacy Specialist Reprinted from The PRN Notebook,™ march 2002. National Institutes of Health Clinical Center Pharmacy Department Dr. James F. Braun, Editor-in-Chief. Tim Horn, Executive Editor. Published in New York City by the Physicians’ Research Network, Inc.,® Summary by Tim Horn John Graham Brown, Executive Director. For further information and other articles available online, visit http://www.PRN.org All rights reserved. © march 2002. Edited by David Back, phd, and John Gerber, md

atients with hiv receive an abun- need for clinicians and other health-care Using gastric pH as an example, Dr. Pau dance of daily medications, often in- providers to understand the potential for explained that, when one drug alters - cluding a triple-drug antiretroviral drug interactions and to critically evaluate ity in the gut, the dissolution of another regimen, primary and/or secondary their patients’ current drug regimens be- concomitantly administered pH-dependent prophylactic drugs, and other com- fore adding new agents. drug may be affected, thereby diminishing pounds as needed (e.g., lipid-lowering its absorption. Two classic cases in point are drugs). Clinicians will be the first to admit ketaconazole (Nizoral), which requires an that the proper use of these drugs has yield- Mechanisms of Drug Interactions acidic gastric environment for solubilization, ed highly desirable effects—including pro- drugs interact in two major ways: phar- and , which requires high gastric longed survival and fewer opportunistic in- macokinetically and pharmacodynamical- pH for stability. As the didanosine , fections—but will also attest to the bur- ly. A pharmacokinetic drug oc- powder, and suspension formulations con- geoning task of monitoring possible drug in- curs when one drug causes a change in an- tain an buffer, coadministration of teractions. other drug’s serum concentration by al- these two drugs would result in poor ab- Of course, the risk of harmful interac- tering its absorption, distribution, metab- sorption of ketaconazole. tions does not stop with the pharmacoki- olism, or elimination. A pharmacodynam- Similarly, clinicians need to recognize netic profiles of individual drugs. Clini- ic drug interaction occurs when the clinical that the intestine also plays a significant cians must also remain aware of possible effect is altered by administering the two role in the absorption and metabolism of interactions between the drugs they pre- drugs concomitantly, such as those yielding certain oral medications. As described in scribe and such things as foods, other dis- synergistic or antagonistic therapeutic ef- “ to the Fore,” an article eases, and nontraditional agents such as vi- fects and those yielding overlapping or ad- summarizing a lecture delivered by David tamins, herbal remedies, and an often un- ditive toxicities. A prime example of a phar- Back, PhD, in the June 2001 issue of The acknowledged factor: recreational drugs. macodynamic interaction is the positive PRN Notebook, cells within the intestinal Taking all of these possible interactions synergistic antiviral effect of zidovudine wall contain into account, one retrospective chart re- (Retrovir)/lamivudine (Epivir) coadminis- and influx/efflux transporters, such as P- view of 50 patients with hiv demonstrated tration. On the flip side, a negative phar- glycoprotein, which can greatly reduce a substantially increased likelihood of drug macodynamic effect might occur when two drug levels even before they reach the liv- interactions with the addition of a single drugs known to cause either bone mar- er for additional metabolizing. Converse- new drug—a protease inhibitor—to their row suppression (e.g., zidovudine and gan- ly, drugs that affect intestinal cytochrome therapeutic regimens. Upon adding the ciclovir [Cytovene]), nephrotoxicity (e.g., P450 and P-glycoprotein activities may re- protease inhibitor, the probability of at least cidofovir [Vistide] and amphotericin B [Fun- sult in positive pharmacokinetic interac- one undesirable drug interaction was 31%, gizone]), or neuropathy (e.g., stavudine tions. A typical example is the coadminis- 42%, and 77% for patients treated with in- [Zerit] and didanosine [Videx; Videx ec]) tration of and , result- dinavir, saquinavir, and ritonavir, respec- are combined. ing in a significant boost in the bioavail- tively, across all CD4+ cell counts. For the co- In terms of potential pharmacokinetic ability of the latter agent. hort with CD4+ counts below 100 cells/mm,3 interactions, numerous possibilities Dr. Pau also noted other factors that the probability jumped to 55%, 63%, and abound. For starters, there are interac- can influence and in- 93%, respectively (Barry, 1997). tions that can affect drug absorption. Some crease the risk of drug-drug interactions. According to Dr. Pau—who began her of the possible mechanisms by which this These include age; gender; race, which is prn lecture with a mind-boggling, yet all- can occur include alterations in gastric associated with various genetic polymor- too-common case report involving an hiv- pH, of compounds, gastric emp- phisms in certain P450 enzymes (e.g., ap- positive man receiving a total of 16 drugs tying, intestinal motility, intestinal blood proximately 5% to 10% of Caucasians and for the treatment of hiv, tuberculosis, he- flow, intestinal CYP3A4 activities, and in- 1% to 3% of African Americans and Asians patitis C, hyperlipidemia—there is a dire testinal P-glycoprotein activities. lack functional CYP2D6 ); body size

4 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG table 1. Interactions to Watch For: Antiretrovirals and Lipid-Lowering Agents

Protease Inhibitors Lopinavir Nelfinavir Ritonavir Saquinavir Atorvastatin IIIIII Cerivastatin IIIIII Clofibrate LLLLLL Fenofibrate LLLLLL Fluvastatin IIIIII Gemfibrizil LLLLLL Lovastatin I ✖✖ ✖✖✖ Pravastatin LLLLLL Simvastatin I ✖✖ ✖✖✖

Non-Nucleoside Reverse Transcriptase Inhibitors Delavirdine Efavirenz Nevirapine Atorvastatin IIIkey to symbols: Cerivastatin III✖ These drugs should not be Clofibrate LLLcoadministered I Fenofibrate LLLPotential interaction that may require close monitoring, III Fluvastatin alteration of drug dosage or Gemfibrizil LLLtiming of administration Lovastatin IIIL No clinically significant interaction Pravastatin LLL Simvastatin III

Source: http://www.hiv-druginteractions.org (January 2002 update). Adapted and reprinted with permission of the Liverpool hiv Pharmacology Group. Interactions shown are based on preliminary data presented at scientific congresses and final reports published in peer-reviewed medical journals. This and other drug-interaction tables on the Liverpool hiv Pharmacology Web site are continuously updated and are accompanied by data summaries for each possible interaction. Readers of this article are urged to consult the Liverpool hiv Pharmacology Group for the most recent updates.

and composition; concomitant conditions nrti Interactions to Watch For dine results in a significant (~79%) increase (e.g., pregnancy), concomitant disease when it comes to drug-drug interactions, in the auc of zidovudine and a decrease states (e.g., hepatitis B, hepatitis C, and most clinicians will first call to mind the (~20%) in the auc of its glucuronide congestive heart failure); acute or chronic pharmacokinetics conundrum associated metabolite, gzdv. The reason for this is not changes of organ function; and diet, alco- with the protease inhibitors. However, nu- entirely understood, although it has been hol, and tobacco use. cleoside reverse transcriptase inhibitors suggested that valproic acid may inhibit Ironically, factors that can affect phar- (NRTIs) are hardly innocent when it comes glucuronidation of zidovudine. macokinetics in certain patient popula- to drug-drug interactions and must be Some antivirals commonly used by hiv- tions are often poorly studied in clinical prescribed cautiously in light of this. positive people can also make for a messy trials. Dr. Pau pointed out that numerous Zidovudine, perhaps the most compre- pharmacokinetic mix with zidovudine. pharmacokinetic studies of antiretroviral hensively studied of all the NRTIs, is asso- First, zidovudine combined with stavu- agents are conducted in healthy, non-hiv ciated with a number of potential drug in- dine can have an antagonistic effect. This infected volunteers. These studies are usu- teractions. For example, probenecid (Ben- likely occurs because of competition for ally brief in duration—single-dose or short emid; Probalan) appears to reduce renal cellular thymidine kinase that is needed for multiple-dose therapy is still the norm— excretion of zidovudine, resulting in monophosphorylation of both drugs. Rib- and have stringent inclusion/exclusion cri- marked and prolonged concentrations of zi- avirin (Rebatol) may also antagonize the teria, including normal organ function and dovudine in the blood. Similarly, concomi- antiretroviral activity of zidovudine. This no concomitant drugs or disease states. tant administration of valproic acid (De- antagonism appears to result from inhi- pacon; Depakene; Depakote) and zidovu- bition of zidovudine phosphorylation by

THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG 5 table 2. Interactions to Watch For: Antiretrovirals and Herbal/Nutraceutical Therapies

Protease Inhibitors Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Echinacea ✖✖✖✖✖✖ IIIIII Juice LLLLLL Milk Thistle IIIIII Seville Orange Juice LLLLLL St John’s Wort ✖✖✖✖✖✖ Vitamin E ✖ LLLLL

Non-Nucleoside Reverse Transcriptase Inhibitors Delavirdine Efavirenz Nevirapine key to symbols: Echinacea ✖✖✖ ✖ Garlic IIIThese drugs should not be coadministered LLL I Potential interaction that may Milk Thistle IIIrequire close monitoring, Seville Orange Juice LLLalteration of drug dosage or timing of administration St John’s Wort ✖✖✖ L No clinically significant interaction Vitamin E LLL

Source: http://www.hiv-druginteractions.org (January 2002 update). Adapted and reprinted with permission of the Liverpool hiv Pharmacology Group. ribavirin and/or phosphorylated ribavirin, ions contained in the buffer. Turning the ta- Cytochrome p450: possibly secondary to a ribavirin-induced bles, methadone can decrease didanosine The Good, the Bad, and the Ugly increase in deoxythymidine triphosphate absorption, and oral ganciclovir can in- most medications used to treat a variety (dTTP) concentrations and a subsequent crease the auc of didanosine by approxi- of diseases are cleared from the body by feedback inhibition of thymidine kinase. mately 100%, although the reasons for this way of biotransformation in the liver. The While this has led to the official stance are not understood. Tenofovir df (Viread), primary goal of hepatic metabolism is to that concurrent use of zidovudine and rib- the newest member of the antiretroviral ar- convert lipophilic compounds into polar avirin is contraindicated, one recent study senal, can increase the auc of didanosine metabolites, which are then excreted in published in AIDS found that coadminis- by 44% and its Cmax by 28%—the clinical urine or feces. tration did not yield any noticeable re- significance of this particular interaction There are two ways in which the liver ductions in the potency and durability of has not yet been determined. Interactions does this. The first involves cytochrome haart (Morisca, 2000). involving the new enteric-coated formu- P450 enzymes, which are responsible for While the bulk of zidovudine’s potential lation of didanosine with other medica- the oxidative metabolism of many com- interaction problems are along the lines tions have not yet been fully elucidated. pounds. These are known as Phase I re- of impaired metabolism and , di- NRTIs also have their share of interac- actions. Phase II reactions involve conju- danosine’s tribulations begin much earlier tions that affect of gation enzymes, which link one chemical in the pharmacokinetic chain of events. coadministered drugs. Zidovudine com- to another. For example, glucuronyl trans- Absorption problems are usually the is- bined with tmp-smx (Bactrim; Septra) or ferases link a glucuronide group to zi- sue with the buffered formulations of di- ganciclovir can increase the risk of bone dovudine, which makes it more water sol- danosine, which results in a number of marrow toxicities, including anemia and uble and, as a result, more easily excreted drug mixes to watch for. Didanosine can neutropenia. There is also the prevailing in urine. decrease absorption of (Spo- fear surrounding the combination of two Of particular concern to Dr. Pau is the ranox), , dapsone (Avlosul- or more of the “d” drugs—ddI (didano- potential for interactions between drugs fon; dds), and delavirdine (Rescriptor) be- sine), ddC (; Hivid), and d4T that are metabolized via the cytochrome cause of increased gastric pH. It can also (stavudine)—which may be associated with P450 system, since many antiretroviral decrease absorption of the quinolones and an increased risk of peripheral neuropathy drugs affect this system. The induction or the by chelation of these an- and, perhaps, mitochondrial toxicity. inhibition of various P450 isoenzymes can tibiotics with the magnesium and calcium substantially affect drug serum concen-

6 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG table 3. Interactions to Watch For: Antiretrovirals and Illicit/Recreational Drugs

Protease Inhibitors Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Alcohol LL L L L L Gamma-hydroxybutyrate (ghb) LL L L I L Marijuana LL I L I L (“Ecstasy”) II I I I I Methamphetamine II I I I I

Non-Nucleoside Reverse Transcriptase Inhibitors Delavirdine Efavirenz Nevirapine key to symbols: Alcohol LL L I Potential interaction that may Gamma-hydroxybutyrate (ghb) LL L require close monitoring, Marijuana LL L alteration of drug dosage or mdma (“Ecstasy”) I LL timing of administration L Methamphetamine I LL No clinically significant interaction

Source: http://www.hiv-druginteractions.org (January 2002 update). Adapted and reprinted with permission of the Liverpool hiv Pharmacology Group. trations, thereby impacting both efficacy it is important to distinguish between the (Calan), and grapefruit juice. With regard and the risk of toxicity. different enzymes, particularly those to the HIV protease inhibitors—all are sub- The cytochrome P450 (CYP) mixed-func- known to have a role in metabolizing the strates of CYP3A4—ritonavir is the most tion monooxygenases are located on the most commonly used medications to treat powerful CYP3A4 inhibitor, not only of all smooth endoplasmic reticulum of cells hiv and its associated manifestations. the protease inhibitors, but of most drugs throughout the body, primarily the liver. Three of the most relevant enzymes, as in general. Indinavir (Crixivan), nelfinavir Some P450 isoenzymes can also be found in they relate to antiretroviral medications, (Viracept), amprenavir (Agenerase), and the lung, the , the brain, the small are discussed here: lopinavir (Kaletra) appear to inhibit CYP3A4 intestine, and the placenta. equally, whereas saquinavir (Fortovase) In humans, there are more than 20 Cytochrome p450 3a4 (): CYP3A is both is the least likely to inhibit this isoenzyme different cytochrome enzymes, of which the most abundant and most clinically sig- system. In the non-nucleoside reverse eight are responsible for the metabolism of nificant member of the cytochrome P450 transcriptase inhibitor class, delavirdine is nearly all clinically useful medications. Al- family of enzymes. The CYP3A family is ac- a potent, irreversible inhibitor of CYP3A4. In though these eight enzymes—CYP1A2, tually composed of three major enzymes, this way, delavirdine is the only non-nu- CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 being the most commonly associ- cleoside reverse transcriptase inhibitor CYP2E1, and CYP3A4—are somewhat related ated with drug interactions. The CYP3A (nnrti) that has a profound effect on ri- and share many general characteristics, isoenzyme subfamily makes up approxi- tonavir serum concentrations. each is unique in its specificity mately 50% of the liver’s total cytochrome Dr. Pau made it clear that there is defi- and thus metabolizes specific drugs. Aside P450 and is also located in the small intes- nitely a handful of drugs that all health-care from their ability to metabolize drugs, tine and is ultimately responsible for the providers should worry about in relation to these isoenzymes are responsible for me- majority of first-pass metabolism. This is CYP3A4. Calcium channel blockers, for ex- tabolizing environmental toxins, dietary important as increases or decreases in ample, are avidly metabolized by CYP3A4 components, and various endogenous sub- first-pass metabolism can have the effect during the first pass. Other substrates to stances (e.g., , prostaglandins, of administering a much smaller or larger watch for include proarrhythmic agents etc.). To further complicate the issue, cer- dose than usual. that undergo extensive first-pass metabo- tain physiologic changes such as the pres- The most notable inducers of CYP3A4 lism such as (Seldane) and ence of inflammation, increases in proin- include the glucocorticosteroids, rifampin (Hismanal). hmg CoA reduc- flammatory cytokine production (e.g., in- (Rifadin; Rimactane), carbamazapine (e.g., tase inhibitors (“statins”), which are fre- terleukin-1, interleukin-6, and tumor Tegretol), , (e.g., quently prescribed to manage lipid abnor- necrosis factor-alpha), and hormonal Dilantin), nevirapine (Viramune), and malities associated with haart, should also changes during pregnancy, may all con- efavirenz (Sustiva). Compounds known to be used with caution (see Table 1). Sim- tribute to changes in cyp activities. inhibit CYP3A4 include erythromycin, clar- vastatin (Zocor) is generally contraindi- In order to completely understand and ithromycin (Biaxin), ketaconazole, cy- cated in patients receiving protease in- predict cytochrome P450 drug interactions, closporine (e.g., Sandimmune), verapamil hibitors. Atorvastatin (Lipitor) is a possi-

THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG 7 bility, though the starting dose should be ethanol also appear to be significant, but mdma—like other —is reduced and then titrated, if necessary, to less consistent, CYP2C9 inducers. Of the an- metabolized by way of the CYP2D6 isoen- achieve the desired cholesterol-lowering tiretroviral drugs, both ritonavir and nel- zyme. While this renders ecstasy and other effect. Conversely, standard doses of finavir have been shown to induce CYP2C9. forms of methamphetamine (e.g., “crystal pravastatin (Pravachol) are generally con- Amiodarone (Cordarone), TMP/SMX, flu- meth”) free of any immediate interactions sidered safe for hiv-positive individuals vastatin (Lescol), metronidazole (Flagyl), with most of the protease inhibitors and being treated with a CYP3A4-inhibiting pro- and fluconazole (Diflucan) are only a few NNRTIs, trouble remains a possibility with ri- tease inhibitor or NNRTI, although a pravas- of the many potent inhibitors of this en- tonavir, an inhibitor of this P450 enzyme. tatin dose increase might also be necessary zyme activity. (Editor’s note: A detailed At least one death, believed to be the re- if the desired effect is not achieved. “Re- discussion of the drug-interaction prob- sult of a ritonavir/mdma mix, has been re- gardless of which ‘statin’ is used,” Dr. Pau lems between the protease inhibitors and ported thus far. The case discussed by Dr. cautioned, “it is important for health-care the rifamycins can be found in an article Pau involved a 32-year-old hiv-positive providers to monitor LFTs and cpk levels in published in the December 2001 issue of British male with a history of alcohol-re- their patients who are taking these drugs The PRN Notebook: “Double Scourge: Tu- lated liver disease, who died of an mdma along with a protease inhibitor.” berculosis and HIV Coinfection.” Guide- overdose on October 6, 1996. He had been lines pertaining to the coadmininistra- taking a standard dose of ritonavir (600 mg Cytochrome p450 26d (): CYP2D6 com- tion of these two classes of drugs vary, de- bid) for approximately two weeks. On the prises a relatively small but significant pending on whether it is latent TB infection night of his death, he had taken two and a percentage of the total cytochrome P450 or active TB that is being treated, and are half mdma tablets (150 mg in total) and in the liver. Only 2% to 6% of total liver cy- important to consider before prescribing had consumed four beers. Soon after tak- tochrome P450 is CYP2D6, but approximately any anti-tuberculosis agents.) ing the extra half tablet, he became hy- one-fifth of clinically useful medications pertonic; his respiratory rate peaked at 45 are metabolized by this enzyme. In par- and his heart rate exceeded 140 bpm. He ticular, many antiarrhythmics and beta- then became cyanotic, experienced a ton- blockers are metabolized by CYP2D6. In Dangerous Liaisons: Interactions ic-clonic seizure and vomiting, went into addition, CYP2D6 is responsible for the con- with mdma and ghb cardiac arrest, and died later that night. version of codeine to morphine, account- some drug interactions can neither be The concentration of mdma in his blood ing for the majority of its analgesic ef- foreseen nor prevented with a prescription was 3.56 mg/L—the equivalent of taking 22 fects. Unlike other CYP enzymes, there are pad. There will always be hiv-positive in- ecstasy tablets. Following additional toxi- no known inducers of this activity, except dividuals—probably a large number of cological investigations, it was concluded pregnancy. Several medications are known them—who take pharmacology into their that inhibition of CYP2D6 by ritonavir and al- to inhibit CYP2D6, the most potent of which own hands in the form of recreational cohol ingestion contributed to the high include , paroxetine (Paxil), and drug use. In and of themselves, numerous mdma levels and his unfortunate death. (Prozac). Other inhibitors in- recreational drugs are associated with a However, some experts note that there is clude: sertraline (Zoloft), (Mel- vast number of deleterious effects. When no way to say with certainty if this was laril), (Tagamet), amiodarone they are combined with certain prescribed truly a drug-drug interaction; other possi- (Cordarone), diphenhydramine, haloperi- medications, any of the life-endangering bilities include abnormal CYP2D6 function or dol (Haldol), and (Ticlid). Of risks and caveats tied to illicit drugs can— self-administration of a large mdma dose. the anti-HIV drugs, only ritonavir is known and often do—increase significantly (see What’s more, there have been no studies to inhibit CYP2D6 activity. Table 2). that have examined the extent of the in- teraction between mdma and ritonavir Cytochrome p450 2c9 (): CYP2C9 is re- mdma: At the top of Dr. Pau’s list of poten- (John Gerber, personal communication). sponsible for the metabolism of several tially dangerous interactions is 3,4-meth- common medications, including many of ylenedioxy methamphetamine (mdma)— ghb: Dr. Pau also discussed a case report the nonsteroidal anti-inflammatory drugs ecstasy. This synthetic, psychoactive ana- published in 1999 by Robert Harrington, (NSAIDs) and phenytoin. While is logue of methamphetamine has both stim- md, and his colleagues at the University of also metabolized by CYP2C9, it is important ulant and hallucinogenic effects and is Washington School of Medicine and School to remember that this drug is adminis- both readily accessible and immensely of Pharmacy in Seattle (Harrington, 1999). tered as a mixture of two isomers [R(+) popular as a recreational drug. While in- The report described an HIV-positive man and S(-)] and is metabolized as two sepa- tense exhilaration and euphoria are of- receiving treatment with ritonavir and rate drugs. While (S)-warfarin is metabo- ten the desired effects of the drug, agitation saquinavir who experienced a prolonged lized by CYP2C9, the (R)-warfarin isomer is and panic are usually not far behind. High stimulatory effect from a small dose of MDMA metabolized in the liver by several isoen- doses can lead to angina, cardiovascular and a near-fatal reaction from a small dose zymes, including CYP1A2 and CYP3A4. It is collapse, convulsions, renal compromise, of [gamma]-hydroxybutyrate (GHB). the (S)-warfarin that is responsible for hepatic failure, and cerebral hemorrhage. The 29-year-old man became unre- most of the anticoagulation activity. Death is also possible with high levels, sponsive within 20 minutes after ingesting The rifamycins, as well as ritonavir, because of rupture or collapse of blood approximately half a teaspoon of GHB. are consistent inducers of CYP2C9 activity. vessels in the brain, acute cardiac failure, Emergency personnel noted shallow res- The , , and or hyperthermia. pirations and a heart rate of 40 bpm. They

8 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG administered sulfate and pan- Complementary Therapies References curonium bromide and performed endo- the potential for interactions between Barry M, Gibbons S, Back D, et al. Protease in- tracheal intubation before conveying the complementary/alternative medicines hibitors in patients with HIV disease. Clini- cally important pharmacokinetic consider- patient to a local hospital, where he was (CAM), including those that are herbal- ations. Clin Pharmacokinet 32(3):194-209, further examined. Urinary toxin screen based, and pharmaceutical compounds 1997. using gas chromatography detected has become a major concern, particularly methamphetamine, atropine, MDMA, and since the publication of a report indicating Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening interactions between prochlorperazine. a major interaction between St. John’s HIV-1 protease inhibitors and the illicit drugs The patient’s vital signs normalized wort and protease inhibitors (Piscitelli, MDMA and gamma-hydroxybutyrate. Arch three hours after admission, and on ques- 2000). In fact, several CAM agents have Intern Med 159(18):2221-4, 1999. tioning, he reported ingesting two tablets been shown in animal and human studies Morsica G, De Bona A, Foppa CU et al. Rib- of MDMA approximately 29 hours before over the past few years to impact metabo- avirin therapy for chronic hepatitis C does admission. The stimulatory effect of MDMA lism via the cytochrome P450 enzyme sys- not modify HIV viral load in HIV-1 positive pa- had persisted for more than one day— tem (see Table 3). These include not only St. tients under antiretroviral treatment. AIDS much longer than the effect of similar dos- John’s wort, but also garlic, , mela- 14:1656-8, 2000. es taken in the past, the patient reported— tonin, milk thistle, geniposide, and skullcap. Piscitelli SC, Burstein AH, Chaitt D, et al. In- and to counter that effect, he had con- Unfortunately, there are a number of dinavir concentrations and St. John’s wort. sumed about half a teaspoon of GHB six limitations to designing and conducting Lancet 355(9203):547-8, 2000. hours before admission, and a similar CAM-drug interaction studies, which es- dose of GHB just before falling unconscious. sentially hampers any attempt to produce Although no human data are available official dosing recommendations for indi- on the metabolism of GHB, Dr. Harrington viduals who use both treatment modalities. and his colleagues wrote, “animal data Dr. Pau explained that, with many CAM suggest that a large portion of GHB is also agents, the active ingredient is unknown, degraded by first-pass metabolic pathways, thus preventing even the most basic in which usually involve the cytochrome P450 vitro testing. “There are also many dif- system.” Therefore, Dr. Harrington’s group ferent brands of herbal products and there speculated that the plasma level of GHB in is no guarantee in terms of quality con- this patient may have been significantly trol,” she added. “A large number of stud- increased by ritonavir, resulting in a life- ies are definitely needed to assess the pos- threatening adverse reaction. sibility of interactions, not only with HIV drugs. Funding, however, is quite limit- ed. Until more data are available, it’s up to health-care providers to keep an eye on their patients’ medications.”

notes

THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 1 • MARCH 2002 • WWW.PRN.ORG 9

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