All of the following drug is CYP3A inhibitor except aEUR'
Saquinavir Drug metabolism Drug metabolism is divided into two genera! categories of phase I and phase II transformation reactions. Phase I This involves structural alteration of drug typically by processes involving oxidation, hydrolysis and reduction. - Phase I reactions introduce functional groups in drugs. - Reactions carried out by phase 1 enzymes usually lead to inactivation of an active drug. Phase II Phase II reactions usually involve conjugation reactions (glucuronidation, suftation, methylation). - Phase 11 reactions produce a metabolite with improved water solubility and increased molecular weight which serves to facilitate the elimination of the drug from the tissue. Most phase I reactions are carried out by P 450 family of isozymes The cytochrome P-450 (CYP450) enzymes are found primarily in the gut and liver. Their name is derived from their characteristic of maximal absorption at wavelength of 450 nm. The cytochrome P 450 is a large superfamily of "haem" proteins. All enzymes in the superfamily contain a molecule of haem. The cytochrome P 450 isoenzymes are also indicated by the letter "CYP" (from cytochrome P 450) followed by number denoting a ,family group, then a subfamily letter and then a number for the individual enzyme within the family. Thus, CYP3A4 is Family Subfamily No. of the individual enzyme within the family The "CYP" isoenzymes have many features that give them great variability in action, both within and among individual. The CYP's have a tremendous capacity to metabolize a large number of structurally diverse chemicals. This is both due to multiple forms of CYP's and the capacity of a single CYP to metabolize many structurally distinct chemicals.. In contrast to other enzymes of the body which are highly specific, CYP's are promiscuous in nature i.e. they catalyze large no of substrates. - This unsual feature of extensive overlapping substrate specificities by the CYP's is one of the underlying reasons for the predominance of drug -- drug interactions. - When two coadministered drugs are both metabolized by a single CYP, they compete for binding to the enzymes active site. - This can result in the inhibition of the metabolism of one or both of the drugs, leading to elevated plasma levels of the drug. Induction and inhibition of CYP's is also an impoant source of drug-drug interactions. Some drugs can also inhibit CYP's independently of being substrates for CYP's. - For example ketoconazole is a potent inhibitor of CYP3A4 and other CYPS and coadministration of ketoconazole with other drugs such as the HIV viral protease inhibitors reduce the clearance of those drugs and increases their plasma concentration and the risk of toxicity. Some drugs are CYP inducers that can induce not only their own metabolism but also induce metabolism of other coadministered drugs. CYP3A is the most abundant, clinically significant group of cytochrome P-450 isoetzzymes. The CYP3A group is composed of four major isoenzymes CYP3A3 - CYP3A4 - CYP3A5 - CYP3A7 Among these CYP3A4 is the most common and is implicated in the majority of drug interactions. - However since these enzymes are so closely related (having as much as 97% sequence homology they often are referred to collectively by the subfamily name CYP3A). Upto 60% of the liver's total cytochrome P-450 is CYP3A and nearly 50% of all clinically relevant medications are metabolized by CYP3A. CYTOCHROME SUBSTRATES INDUCERS INHIBITORS CYP3A Alprazolani, Astetnizole Atorvastatin, Carbatnazepine, Cisapride Cyclosporine, Diltiazem, Losaan, lovastatin, Midazolam, Nifedipine, Sinzvastatin, Terfenadine, Theophylline Carbamazepine, Ethanol, Phenobarbital, Phenytoin, Rifampin Cinzetidine, Clarithromycin, Cyclosporine, Diltiazenz, Erythromycin, Fluoxetine, Fluvexamine, Grapefruit juice 1111' Protease inhibitors, Itraconazole, Ketoconazole, Nifedipine, Verapantil Verapanzil About protease inhibitors "All of the antiretroviral protease inhibitors are substrates and inhibitors of CYP3A4 with ritonavir having the most pronounced inhibitory effect and saquinavir the least". - It is notewohy that the potent CYP3A4 inhibitory propeies of ritonavir have been utilized to clinical advantage by having it "boost" the levels of other agents when given in combination. An impoant point Ritonavir is an enzyme inducer with chronic (repeated) administration. Ritonavir Acute administration Enzyme inhibitor Chronic administration Enzyme inducer (p. 64 Katzung 11 "'/e)
Erythromycin
Itraconazole
Ritonavir
Saquinavir