CLOZAPINE DISPOSITION COVARIES WITH CYP1A2 ACTIVITY DETERMINED BY A CAFFEINE TEST

In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoi n hydroxylation polymophism. The same 14 healthy subjects studied in t hat investigation were given 150 mg of caffeine. The reciprocal of pla sma clozapine AUC (0,24), was correlated with an index of the N3-demet hylation of caffeine (r(s) = 0.84; P = 0.0024), used as a measure of c ytochrome P4501A2 (CYP1A2) activity. N1- and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (r(s) = 0.89 and 0.85; P = 0.0013 and 0.0023; res pectively). No significant relationships with xanthine oxidase and N-a cetyl transferase activity, also assessed by a caffeine test, were fou nd. This study suggests that clozapine is metabolised by CYP1A2 to a m ajor extent.