The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceDRUG-DRUG INTERACTIONS DUE TO THECYTOCHROME P450 ENZYME SYSTEM26 picas■ The cytochrome P450 (CYP) enzyme system is a group of mixed function monooxygenaseslocated on the smooth endoplasmic reticulum of cells throughout the body, primarily the liver.In humans, there are more than 20 different cytochrome enzymes, eight of which are responsiblefor the metabolism of almost all clinically useful medications. These eight enzymes aredesignated as CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.Though they are somehow related and share many general features, each is unique in the substratesfor which it is specific and so metabolizes only specific drugs and substances. 3 The P450enzymes involved in drug metabolism are found not only in the liver, but also in the kidneys,lungs, brain, small intestine and placenta.Enzymes of the CYP450 system are responsible for the oxidative metabolism of a large and variednumber of compounds including, most importantly, the antiretroviral agents (PIs and NNRTIs),several drugs used in the management of opportunistic infections in advancing HIV disease,many of the newer serotonin-specific reuptake inhibitors (SSRIs) and other psychotropic agents,endogenous substances such as steroids and prostaglandins, environmental toxins, and dietarycomponents. The primary role of the isoenzymes in drug metabolism is to make the drugs morewater-soluble and less fat-soluble, so that biliary excretion will take place. As a result of this,actions of these enzymes can affect the amount of active drug in the body at any given time. Suchchanges can be positive, enhancing efficacy, or negative, enhancing toxicity and adverse events. 4Role of the Cytochrome P450 3A4 (CYP3A4)CYP3A is both the most abundant and clinically significant family of cytochrome P450 enzymes.The CYP3A consists of three major enzymes, CYP3A4 being the one most commonly associatedwith drug interactions. The most notable inducers of CYP3A4 include theglucocorticosteroids, rifampin, carbamazepine, phenobarbital, phenytoin, nevirapine andefavirenz. Notable CYP3A4 inhibitors include erythromycin, clarithromycin, Biaxin (but notazithromycin), ketoconazole, verapamil, and grapefruit juice among others.Ritonavir (Norvir) is the most potent inhibitor of the CYP3A4 system when compared to all theother PIs and indeed to all other drugs, generally. Indinavir and nelfinavir exhibit the same levelof inhibition while saquinavir and amprenavir appear to be the least likely to inhibit CYP3A4.Among the NNRTIs, delavirdine is a potent irreversible inhibitor of this enzyme and is presentlythe only drug that has been shown to affect levels of ritonavir, increasing its Area Under theCurve (AUC) by 60% in patients maintained on a regimen of ritonavir 600 mg twice daily. 5Recent studies have shown that both ritonavir and nelfinavir can act as inducers as well asinhibitors. Though this feature is not completely understood, affinity studies show that thesetwo compounds bind with such high affinity that it becomes impossible for other agents to attachto the enzyme; hence inhibiting access to the enzymes while inducing their own metabolism.Drug Interactions with Ritonavir andOther Substrates of the CYP3A4 SystemIn relation to CYP3A4, there are a number of clinically significant drug-drug interactionswith which providers must become conversant. For the past several years, ritonavir (Norvir),the powerful inhibitor of enzymes of the cytochrome P450 system, has been used to boost levelsof other PIs, mostly saquinavir (Fortovase), indinavir (Crixivan) and amprenavir (Agenerase).XXVIIU.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau 555