Effects of antidepressant drugs on the activity of cytochrome P-450 measured by caffeine oxidation in rat liver microsomes.

Caffeine is a marker drug for testing the activity of CYP1A2 (3-N-demethylation) in humans and rats. Moreover, it is also a relatively specific substrate of CYP3A (8-hydroxylation). In the case of 1-N- and in particular 7-N-demethylation of caffeine, apart from CYP1A2, other cytochrome P-450 isoenzymes play a considerable role.

Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver.

The primary metabolic pathways of caffeine are 3-N-demethylation to paraxanthine (CYP1A2), 1-N-demethylation to theobromine and 7-N-demethylation to theophylline (CYP1A2 and other enzymes), and 8-hydroxylation to 1,3,7-trimethyluric acid (CYP3A). The aim of the present study was to investigate the influence of phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, perazine) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated neuroleptics competitively inhibited caffeine oxidation in the rat liver, though their potency to inhibit particular metabolic pathways was not equal.