Hepatic P-450 enzyme

Drug interactions No drug interaction studies have been conducted with Avonex. Other interferons have been found to reduce cytochrome P-450-mediated drug metabolism. Hepatic microsomes isolated from Avonex-treated rhesus monkeys showed no influence on hepatic P-450 enzyme metabolism activity. 

Several metabolites of BP have been identified using in vitro and in vivo methods. When isolated rat hepatocytes were incubated with BP (0.25 mM) over a 3-h time course, the levels of BP decreased, while levels of its metabolites benzhydrol and the sulfate conjugate of 4-OH BP increased (Nakagawa et al. 2000). There was also a small increase in levels of non-conjugated 4-OH BP. The authors believed the formation of the 4-OH BP was probably due to enzymatic aromatic hydroxylation mediated by cytochrome P-450 enzymes, though the activity of hepatic P-450 enzymes were not reported in this study. 

Other major untoward reactions are the result of rifampin s ability to induce hepatic cytochrome P-450 enzymes, leading to an increased metabolism of many drugs this action has especially complicated the treatment of tuberculosis in HIV-infected patients whose regimen includes protease inhibitors and nonnucleoside reverse transcriptase. Since rifabutin has relatively little of these effects, it is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. 

The liver is the principal site of drug metabolism. Hepatic drug metabolism is usually classified into two distinct phases. Phase I reactions are oxidation, reduction or hydrolysis. One of the most important systems that catalyse oxidation are the haem-containing cytochrome P-450 enzymes. 

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. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

Table 5.19 Effect of a Reduced Protein Diet on Hepatic Cytochrome P-450 Enzyme Activity in Rats...

The distribution and metabolism of protein-based biotech drugs, for example, generally follows the mechanisms of endogenous and nutritional proteins. This includes, for example, unspecific proteolysis as a major elimination pathway for proteins rather than oxidative hepatic metabolism typical for the majority of small-molecule drugs. As a consequence, drug interactions studies focused on cytochrome P-450 enzymes do not usually need to be performed for protein-based biotech drugs [17]. 

McGinnity DF, Griffin SJ, Moody GC, et al. Rapid characterization of the major dmg-metabolizing human hepatic cytochrome P-450 enzymes expressed in Escherichia coli. Dmg Metab Dispos 1999 27 1017-1023. 

Absorption and metabolism Carbamazepine is absorbed slowly following oral administration. It enters the brain rapidly because of its high lipid solubility. Carbamazepine induces the drug metabolizing enzymes in the liver, and its half-life therefore decreases with chronic administration. The enhanced hepatic P-450 system activity also increases the metabolism of other antiepileptic drugs. 

The correct answer = D. Ketoconazole is effective against Candida, but it does not react with cyclosporine nor is it cardiotoxic. Ketoconazole inhibits the hepatic cytochrome P-450 enzymes that inactivate cyclosporine. Thus in this instance the patient would be in danger of increased cyclosporine toxicity. Though ketoconazole does cause gynecomastia and decreased libido, this would not be of primary concern. 

Waxman, D. J. (1988). Interactions of Hepatic Cytochromes P-450 with Steroid Hormones. Regioselectivity and Steieospecificity of Steroid Metabolism and Hormonal Regulation of Rat P-450 Enzyme Expression, Biochem. Pharmacol., 37 71-84. 

Waxman DJ. Interactions of hepatic cytochromes P-450 with steroid hormones. Regioselectivity and stereospecificity of steroid metabolism and hormonal regulation of rat P-450 enzyme expression. Biochem Pharmacol 1988 37(1) 71-84. 

McGinnity, D.F. Griffin, S.J. Moody, G.C. Voice, M. Hanlon, S. Friedberg, T. Riley, R.J. Rapid Characterization of the Major Drug-metabolizing Human Hepatic Cytochrome P-450 Enzymes Expressed in Escherichia coli, Drug Metab. Dispo. 27(9), 1017-1023 (1999). 

Many of the chemical interactions with carbon disulfide appear to be related to loss of microsomal cytochrome P-450. Carbon disulfide suppresses the hepatic cytochrome P-450 microsomal enzyme system. Elimination of phenazone, a drug often used in the study of hepatic microsomal enzyme activity, is significantly and reversibly inhibited in rabbits exposed to 193 ppm carbon disulfide for 5 hours a day, 6 days a week, for 6 months (Orzechowska et al. 1984). It has been proposed that the active sulfur atoms released following carbon disulfide metabolism suppress the cytochrome P-450 enzymes, thus inhibiting detoxification of other drugs or chemicals. 

Cadario, B.J., G.D. Bellward, S. Bandiera, T.K.H. Chang, W.W.W. Ko, E. Lemieux et al. (1992). Imprinting of hepatic microsomal cytochrome P-450 enzyme activities and cytochrome P-450I1C11 by peripubertal administration of testosterone in female rats. Mol. Pharmacol. 41, 981-988. 

LeBlanc, G.A. and D.J. Waxman (1988). Feminization of rat hepatic P-450 expression by cisplatin. Evidence for perturbations in the hormonal regulation of steroid-metabolizing enzymes. J. Biol. Chem. 263, 15732-15739. 

Ma, Q., G.A. Dannan, F.P. Guengerich, and C.S. Yang (1989). Similarities and differences in the regulation of hepatic cytochrome P-450 enzymes by diabetes and fasting in male rats. Biochem. Pharmacol. 38, 3179-3184. 

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