Cytochrome P450 enzymes pharmacokinetics

Eukasawa, T., Suzuki, A. and Otani, K. (2007) Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. Journal of Clinical Pharmacy and Therapeutics, 32, 333—341. 

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

Ma, J.D., A.N. Nafziger, and J.S. Bertino, Jr. 2004. Genetic polymorphisms of cytochrome P450 enzymes and the effect on interindividual, pharmacokinetic variability in extensive metabolizers. J Clin Pharmacol 44 447. 

Pharmacokinetic interactions. TCAs and SSRIs are metabolised extensively by cytochrome P450 enzymes and adding, changing or stopping antidepressants to a drug regimen can have important consequences. 

Emoto C, Murase S, Sawada Y, et al. In vitro inhibitory effects of 1-aminobenzotriaz-ole on drug oxidations catalyzed by human cytochrome P450 enzymes A comparison with SKF-525A and ketoconazole. Drug Metab Pharmacokinet. 2003 18 287-295. 

Tanaka E. Clinically important pharmacokinetic drug-drug interactions Role of cytochrome P450 enzymes. J Clin Pharm Ther 1998 23 403-16. 

Paroxetine is metabolized by the hepatic cytochrome P450 enzyme CYP2D6. Hence, it is susceptible to pharmacokinetic interaction with drugs that either induce or inhibit this enzyme. 

Current data suggest no clinically significant pharmacokinetic interaction between sertraline and alcohol. This is due, probably, to the fact that alcohol is metabolized by the hepatic cytochrome P450 enzyme CYP2E1. The latter does not metabolize sertraline. Moreover, CPY2E1 rarely metabolizes any of the other regularly used psychiatric drugs. 

Antidepressants Fluvoxamlne, a potent inhibitor of the cytochrome P450 enzymes CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4, has been reported to cause a 5-10-fold elevation of plasma clozapine concentration. Fluoxetine and paroxetine may also increase plasma clozapine concentrations, while citalopram and sertraline have been reported to cause minimal or no elevation of plasma levels of clozapine. To date, in vivo studies with a combined olanzapine-imipramine regimen have not revealed any pharmacokinetic interactions. 

With warfarin, one is always concerned about pharmacodynamic and pharmacokinetic drug interactions. None of the antiarrhythmic drugs mentioned above are likely to cause a pharmacodynamic interaction with warfarin. However, amiodarone is a cytochrome P450 enzyme inhibitor and increases warfarin s antithrombotic effects. Patients taking both drugs usually need to decrease their dose of warfarin. 

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