Udp

UDP-glucuronic acid

PAPS + ROH

3 '-phosphoadenosine-5' phosphosulfate

RO-. RS-. RN- + AdoMet RO-CH, + AdoHomCys GSH + R ^ GS-R

3'-phosphoadenosine-5'-phosphate

Carbamazepine

Procaine, aspirin, Clofibrate, meperidine, enalapril, cocaine Lidocaine, procainamide, indomethacin

Acetaminophen, morphine, oxazepam, lorazepam

Acetaminophen, steroids, methyldopa

Sulfonamides, isoniazid, dapsone, clonazepam (see Table 3-3) L-Dopa, methyldopa, mercaptopurine, Captopril Adriamycin, fosfomycin, busulfan drugs (see below and Figure 3-5). Steroid hormones and herbal products such as St. John's wort can increase hepatic levels of CYP3A4, thereby increasing the metabolism of many drugs. Drug metabolism can also be influenced by diet. CYP inhibitors and inducers are commonly found in foods and in some cases these can influence drug toxicity and efficacy. Components of grapefruit juice are potent inhibitors of CYP3A4; thus, drug inserts may warn that taking a medication with grapefruit juice could increase the drug's bioavailability. The antihistamine terfenadine was withdrawn from the market because its metabolism was blocked by CYP3A4 substrates such as erythromycin and grapefruit juice. Terfenadine is a prodrug that requires oxidation by CYP3A4 to its active metabolite, and at high doses the parent compound causes arrhythmias. Thus, elevated levels of parent drug in the plasma as a result of CYP3A4 inhibition caused ventricular tachycardia in some individuals. Interindividual differences in drug metabolism are significantly influenced by polymorphisms in CYPs. The CYP2D6 polymorphism has led to the withdrawal of several drugs (e.g., debrisoquine and perhexiline) and the cautious use of others that are CYP2D6 substrates (e.g., encainide and flecainide [antiarrhythmics], desipramine and nortriptyline [antidepressants], and codeine).

FLAVIN-CONTAINING MONOOXYGENASES (FMOs) FMOs are another superfamily of phase 1 enzymes that are expressed at high levels in the liver and localized to the ER. There are six families of FMOs, with FMO3 being most abundant in liver. FMOs are minor contributors to drug metabolism and generally produce benign metabolites. FMOs are not induced by any of the xenobiotic receptors (see below) or easily inhibited; thus, in distinction to CYPs, FMOs are less involved in drug interactions. This distinction has practical consequences, as illustrated by two drugs used in the control of gastric motility, itopride and cisapride. Itopride is metabolized by FMO3; cisapride is metabolized by CYP3A4. Thus, itopride is less likely to be involved in drug interactions than is cisapride. CYP3A4 participates in drug interactions through induction and inhibition of metabolism, whereas FMO3 is not induced or inhibited by any clinically used drugs (although FMOs may become important as new drugs are developed). FMO3 metabolizes nicotine as well as H2-receptor antagonists (cimetidine and ranitidine), antipsychotics (clozapine), and antiemetics (itopride).

HYDROLYTIC ENZYMES Epoxides are highly reactive electrophiles that can bind to cellular nucleophiles found in protein, RNA, and DNA, resulting in cell toxicity and transformation. Two forms of epoxide hydrolase (EH) hydrolyze epoxides produced by CYPs: a soluble form (sEH) is expressed in the cytosol and a microsomal form (mEH) is localized to the ER membrane. These EHs participate in the deactivation of potentially toxic derivatives generated by CYPs. The antiepileptic drug carbamazepine (Chapter 19) is a prodrug that is converted to its pharmacologically active derivative, carbamazepine-10,11-epoxide by CYP3A4. This metabolite is efficiently hydrolyzed by mEH to a dihydrodiol, resulting in drug inactivation. The tranquilizer valnoctamide and anticonvulsant valproic acid inhibit mEH, resulting in clinically significant drug interactions with carbamazepine by causing elevations of the active derivative. This has led to the development of new antiepileptic drugs (e.g., gabapentin and levetiracetal) that are metabolized by CYPs but not by EHs.

The carboxylesterase superfamily catalyzes the hydrolysis of ester- and amide-containing compounds. These enzymes are found in both the ER and cytosol of many cell types and are involved in detoxification or metabolic activation of drugs, environmental toxins, and carcinogens. Car-boxylesterases also catalyze the activation of prodrugs to their respective free acids. For example, the prodrug and cancer chemotherapeutic agent irinotecan is bioactivated by plasma and intracel-lular carboxylesterases to the potent topoisomerase inhibitor SN-38.

PHASE 2 METABOLISM: CONJUGATING ENZYMES The phase 2 conjugation reactions are synthetic in nature. The contributions of different phase 2 reactions to drug metabolism are shown in Figure 3-2B. Two of the reactions, glucuronidation and sulfation, result in the formation of metabolites with significantly increased hydrophilicity. Glucuronidation also markedly increases the molecular weight of the compound, which favors biliary excretion. Characteristic of the phase 2 reactions is the participation of cofactors such as UDP-glucuronic acid (UDP-GA) for UGTs and 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for SULTs; these cofactors react with functional groups on the substrates that often are generated by the phase 1 CYPs. With the exception of glucuronidation, which is localized to the luminal side of the ER, all phase 2 reactions are carried out in the cytosol. The catalytic rates of phase 2 reactions are significantly faster than the rates of the CYPs. Thus, if a drug is targeted for phase 1 oxidation through the CYPs followed by a phase 2 conjugation reaction, the rate of elimination usually will depend on the phase 1 reaction.

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