Cytochrome enzyme induction

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

The traditional approach for assessing hepatotoxicity integrates clinical chemistry markers, histopathology evaluation, cytochrome P450 enzyme induction, in-life... 

Carbamazepine induces hepatic cytochrome P450 (CYP) enzymes, which may reduce levels of other medications. Through the mechanism of hepatic enzyme induction, carbamazepine therapy can lead to oral contraceptive failure therefore, women should be advised to consider alternative forms of birth control while taking carbamazepine. Similarly, use of medications or substances that inhibit CYP 3A3/4 (discussed in Chapter 1) may result in significant increases in plasma carbamazepine levels. 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Enzyme induction. Some of the enzymes responsible for bio transformation may be induced by exposure to chemicals and other factors (such as diabetes). Induction requires repeated exposure. If only one iso form of the enzyme (e.g., of cytochrome P-450) is induced, the route of metabolism/proportion of metabolites may be changed as well as the rate. The amount of enzyme is increased (and the overall activity in the particular tissue), but inducers may cause other changes such as increases in bile and blood flow and in the smooth endoplasmic reticulum. 

Batt AM, Siest G, Magdalou J, et al. Enzyme induction by drugs and toxins. Clin Chem Acta 1992 209 109. Bresnick E, Houser WH. The induction of cytochrome P-450c by cytosolic hydrocarbons proceeds through the interaction of a 4S cytosolic binding protein. In Ruckpaul K, Rein H, eds. Frontiers of Biotransformation, Vol. II, Principles, Mechanisms and Biological Consequences of Induction. London Taylor Francis, 1990. 

Okey AB. Enzyme induction in the cytochrome P450 system. Pharmacol Ther 1990 45 241. 

Tolerance is the modification of the biological effect of a chemical as a result of repeated dosing. For example, repeated dosing with phenobarbital leads to a decrease in the anesthetic effect of the drug as a result of enzyme induction. Giving animals a small dose of carbon tetrachloride renders a second larger dose less toxic. This may be a result of induction of repair processes and destruction of cytochrome P-450 caused by the small first dose. 

Wistuba, D., Nowotny, H.P., Trager, O. Schurig, V. (1989) Cytochrome P-450 catalyzed asymmetric epoxidation of simple prochiral and chiral aliphatic alkenes. Species dependence and effect of enzyme induction on enantioselective oxirane formation. Chirality, 1, 127-136... 

Suggestions about the metabolic pathway leading to " CO2 were provided by the work of Marker and Kulkami (1985, 1986). They showed that the microsomal metabolism of 2-nitropropane in mice resulted in the release of nitrite in a cytochrome P450-dependent reaction. In contrast to earlier results in rats, cnzx matic denitrification in mice did not require enzyme induction. 

---