Hepatic enzyme induction

Enzymatic-metabolic activation (in part unknown)/phenobarbital-like promotion Hepatic enzyme induction, thyroid enzyme inhibition/axazepam, amobarbital, sulphonamides, thioureas Gastric secretory suppression, gastric atrophy induction (climetidine, omeprazole, butachlor... 

Shertzer HG, Sainsbury M. 1991. Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. Food Chem Toxicol 29 391-400. 

Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own. 

Such a medical adrenalectomy is an efficacious treatment for metastatic breast and prostate cancer, since it diminishes the levels of circulating sex hormones. Glucocorticoids are administered concomitantly to suppress enhanced corticotrophin release. Cortisol is preferable to dexamethasone in this situation because aminoglutethimide markedly enhances the hepatic microsomal metabolism of dexamethasone. Hepatic enzyme induction may be responsible for the development of tolerance to the side effects of aminoglutethimide, such as ataxia, lethargy, dizziness, and rashes. 

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. 

Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Therapeut 1992 52(5) 453-457. 

Taken with alcohol they potentiate the sedative effects and impairment of psychomotor performance. Hepatic enzyme induction by barbiturates or nicotine may reduce plasma levels. Cimetidine may increase levels by enzyme inhi bition. Some antipsychotic drugs may compete for similar metabolic pathways. 

During the acute phase of thyrotoxicosis, B-adrenoceptor blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20-40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. Propranolol is gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90-120 mg three or four times daily, can be used to control tachycardia in patients in whom blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4... 

Thyroid effects that have mainly included reduced serum T4 hormone levels and follicular cell hyperplasia were consistently observed in rats and mice orally exposed to PBDEs. Accompanying changes in serum TSH levels were not found and the depression of serum T4 is likely related to hepatic enzyme induction. Acute duration studies showed decreases in serum T4 in rats exposed to >10 mg/kg/day octaBDE or >30 mg/kg/day pentaBDE for 4 days and in rats and mice exposed to >18 mg/kg/day pentaBDE for 14 days. Effects observed in intermediate-duration studies include thyroid hyperplasia in rats exposed to >8 mg/kg/day octaBDE for 30 days and reduced serum T4 in rats exposed to >10 mg/kg/day pentaBDE for 90 days. Exposure to pentaBDE on gestation day 6 through postnatal day 21 caused serum T4... 

High-dose effects of renal and adrenal changes (related to ethylene glycol) and hepatic enzyme induction... 

Barbiturates + phenytoin —> decreased anticonvulsant effect due to hepatic enzyme induction enhanced phenytoin toxicity on abruptly stopping barbiturate. 

Barbiturates + oral anticoagulants —> decreased anticoagulant effects due to hepatic enzyme induction. 

Being one of the long-time standards in basic psychopharmacology, there are few major variants to the procedure apart from the kind of barbiturate employed. Several barbiturates undergo clear hepatic metabolism, for example pentobarbital and phenobarbital, thereby confounding interpretations because of pharmacokinetic and metabolic factors. Indeed, one modification of the method has been specifically employed to estimate enzyme induction in the liver as indicated by more rapid barbiturate metabolism. Animals given a pre-exposure to a test substance are then exposed to a standard dose of phenobarbital (80 mg/kg i.p.) 24 hours later and assessed for sleep duration. The presence or absence of a decrease in sleep duration is taken as an index of the hepatic enzyme induction produced by the test substance (Kushikata et al. 2003). 

Caution should be used in patients susceptible to hepatic enzyme induction (e.g. chronic alcohohcs and patients taking enzyme-inducing drugs). Enzyme induction may theoretically enhance the production of toxic metabolites, but currently there is no clear evidence that these interactions... 

Capacity for hepatic enzyme induction appears to be lessened. 

Drug metabolism may also be increased by hepatic enzyme induction from insecticide acciunu-lation, e.g. dicophane (DDT) and from alcohol and the tobacco habit, e.g. smokers require a higher dose of theophylline. 

Substances carcinogenic to animals (polycyclic hydrocarbons and nicotine-derived N-nitrosamines) have been identified in tobacco smoke condensates from cigarettes, cigars and pipes. Polycyclic hydrocarbons are responsible for the hepatic enzyme induction that occurs in smokers. 

Effects on sexual function. Nothing really new has been said since William Shakespeare wrote that alcohol provokes the desire, but it takes away the performance. Performance in other forms of athletics is also impaired. Prolonged substantial consumption lowers plasma testosterone concentration at least partly as a result of hepatic enzyme induction ... 

The mechanism of hepatic enzyme induction by St. John s wort has been intensively researched (18,19). Treatment of human hepatocytes with extracts of St John s wort or with hyperforin (one of its active constituents) resulted in induction of CYP3A4 expression (20). 

Li M-H, Rhine C, Hansen LG. 1998. Hepatic enzyme induction and acute endocrine effects of 2,3,3, 4, 6 -pentachlorobiphenyl in prepubertal female rats. Arch Environ Contam Toxicol 35 97-103. 

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