These isoenzymes are a major determinant of the pharmacokinetic behavior of numerous …

• Abstract
• Introduction
• Cytochrome P450 isoenzymes (CYPs)
• Genetic polymorphism
• Drug Drug interaction
• Enzyme induction
• Enzyme inhibiton
• CYP1A 2, CYP2C 9, CYP2C 19, CYP2D 6, CYP2E 1 & CYP3A 4
• Conclusion
• References
• Figure
• Tables

CYP1A 2

CYP1A2 accounts for 13% of total hepatic content of isoenzymes.[8] CYP1A2 isoenzyme metabolizes chemicals and environmental toxins. CYP1A2 can activate benzpyrene, a carcinogen present in cigarette smoke, by 7-8 epoxidation.[20] Cigarette smoke can increase the synthesis of this isoenzyme by 3 fold. Drug substrates include caffeine, propranolol and theophylline etc. Drugs that inhibit CYP1A2 include cimetidine, erythromycin, floroquinolones. Out of floroquinolones, ciprofloxacin is the most potent inhibitor as compared to norfloxacin, ofloxacin. Sparfloxacin and levofloxacin have negligible effect on enzyme activity[27][Table - 2].

CYP2C 9

CYP2C9 exhibits genetic polymorphism [Table - 1]. CYP2C9 is absent in about 1% of Caucasians. CYP2C9 is responsible for the metabolism of ibuprofen, tolbutamide and torsemide.[28],[29],[30] S-warfarin is mainly metabolized by this isoform along with various NSAIDs.[31] Inhibition of this isoform results in several clinically important drug interactions. Fluconazole, metronidazole and amiodarone are a few examples of the many drugs that profoundly inhibit S-warfarin metabolism and produce marked increase in prothrombin time [Table - 2].

Other serious interaction is inhibition of S-warfarin metabolism by amiodarone.[32] Because of long half life of amiodarone, clinical onset of interaction may be delayed by one week to 2 months and PT remains elevated for 1-3 week after treatment is discontinued. This interaction can be avoided by decreasing the dose of warfarin by 25% when amiodarone is added. Induction of CYP2C9 by rifampicin can cause therapeutic failure of phenytoin [Table - 3].

CYP2C 19

CYP2C19 also exhibit polymorphism. About 20% of Asians and 3-5% of Caucasians are poor metabolizers, whereas in 20% of Japanese this isoform is absent.[8] Drug metabolized by CYP2C19 includes omeprazole, diazepam, lansoprazole. Poor metabolizers taking imipramine, clomipramine or diazepam may develop higher serum levels than extreme metabolizers.

CYP2D 6

This isoform accounts for 2% of total CYP450 expression and exhibit genetic polymorphism. 7-10% of Caucasians are poor metabolizers.[10] 5-10% Mexican-Americans lack CYP2D6 isoenzyme but only 1-2% of Asians lack this enzyme and are characterized as poor metabolizers.[10],[11] The activity of CYP2D6 shows a bimodal distribution indicating the presence of dominant and recessive alleles in the population. CYP2D6 is not inducible by pharmacological agents. More than 80 drugs in clinical use are metabolized by this isoform. Several antipsychotic are metabolized by CYP2D6, so poor metabolizers are at risk for postural hypotension and extrapyramidal side effects. Codeine is O-demethylated to morphine by CYP2D6.[33] Thus, poor metabolizers may have less response to codeine as compared to extensive metabolizers.

All antidepressants except fluvoxamine, nefazodone, bupropion and citalopram either inhibit or are metabolized by CYP2D6. Paroxetine is most potent in inhibiting the metabolism of CYP2D6 substrates as compared to sertaline and fluoxetine. Inhibition of CYP2D6 by fluoxetine or paroxetine can increase the cardiac toxicity of tricyclics if both SSRIs and tricyclics are administered together.[34] Fluoxetine also can inhibit metabolism of trazodone and nefazodone to precipitate serotonin syndrome.[35]

CYP2E 1

CYP2E1 accounts for 7% of total CYP content in liver. It exhibit polymorphism and toxicologically an important enzyme. Several volatile anesthetic agents (sevoflurane, isoflurane) are metabolized by CYP2E1.[36] This isoform is also responsible for metabolism of ethanol and acetaminophen, chronic ethanol consumption induces but acute administration of ethanol inhibits CYP2E1. Patient with alcohol dependence are at increase risk for acetaminophen toxicity as ethanol induction of CYP2E1 increases formation of reactive metabolite which is hepatotoxic.[37],[38] Cimetidine exhibit only moderate affinity for this isoform and produces no significant inhibition of the production of acetaminophen's toxic metabolites.[39]

CYP3A 4

CYP3A4 family accounts for 30% of total hepatic content and 70% of gut wall content.[8] It does not exhibit genetic polymorphism. CYP3A4 is involved in metabolism of large number of endogenous and exogenous compounds. The endogenous compounds metabolized by CYP3A4 includes progesterone, oestradiol, testosterone and cortisol.[40] Some of the most serious drug interactions have been caused by accumulation of substrate metabolized by CYP3A4 like astemizole, terfenadine. Potent inhibitors of this isoform like erythromycin, ketoconazole and grape fruit juice have caused elevated substrate levels that have precipitated prolonged QT interval, torsades de pointes and even death.[41] Grape fruit juice causes downregulation of CYP3A4 production in small intestine which can lead to increase bioavailability of felodipine, cyclosporine, saquinavir, terfenadine and triazolam.[41],[42] Serious ventricular arrhythmias have been reported in patients taking cisapride and drugs that inhibit CYP3A4, the isoform responsible for metabolism of cisapride.[43] Erythromycin and clarithromycin (but not azithromycin) decrease theophylline metabolism by inhibiting CYP3A4 [Table - 2].

Rifampicin is very potent inducer of CYP3A4. Of particular clinical relevance is the potential reduction of oral contraceptive efficacy by rifampicin, since estradiol levels can be reduced by rifampicin mediated CYP3A4 induction. Rifampicin is also responsible for producing sub therapeutic protease inhibitors levels[44][Table - 3].

Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug by P-glycoprotein are major determinants of bioavailability of orally administered drugs. The evidence for hypothesis that CYP3A4 and P-glycoprotein (P-gp) may act in concert to limit oral drug bioavailability comes mainly from a limited number of in vitro and animal studies. CYP3A4 and P-gp are an integral part of an intestinal defense system to protect the body against xenobiotics and drugs that are substrates of both proteins often have a low bioavailability after oral administration.[45],[46]

Therefore, like CPY-mediated drug interactions, P-gp-mediated drug interactions may be anticipated when P-gp substrates and P-gp inhibitors or inducers are coadministrated. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, there is an overlapping of substrate specificities and inhibitor/inducers between CYP3A4 and P-gp; many drug interactions may involve both CYP3A4 and P-gp and it is difficult to distinguish the specific nature of drug interactions at present.


Some important drug interactions websites

http://www.hospitalist.net/highligh.htm

http://home.earthlink.net/~cpardee/

http://medicine.iupui.edu/flockhart/

http://vm.cfsan.fda.gov/%7Elrd/fdinter.html

http://www.erowid.org/psychoactives/pharmacology/pharmacology_enzymes1.