The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement

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Abstract
Clozapine is an atypical antipsychotic drug that is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Smoking is a potent inducer of CYP1A2 enzyme activity, resulting in significant lower clozapine serum concentrations in smokers compared with non-smokers, upon a given dose. Recently, a single nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was reported to affect the inducibility of the enzyme. Because this polymorphism in relation to smoking behaviour may be relevant in treatment with clozapine, we studied the effect of CYP1A2 genotype on clozapine clearance and dose requirement in a group of 80 smoking and non-smoking schizophrenic patients on long-term clozapine therapy. Clozapine serum concentration and CYP1A2 genotype had been determined routinely by high-performance liquid chromatography and polymerase chain reaction analyses, respectively. In smokers, the clozapine serum concentration corrected for dose (C/D ratio) was on average 2.5 times lower compared with non-smokers, indicating an enhanced clearance. The mean required maintenance doses of clozapine for smokers and non-smokers were 382 mg/day and 197 mg/day, respectively (P< 0.01). Neither among smokers, nor among non-smokers mean C/D ratios and daily doses did vary significantly between patients with the different CYP1A2 genotypes. The results show that clozapine clearance and daily dose requirement are strongly associated with smoking behaviour, while the CYP1A2 genetic polymorphism seems to have no significant clinical effect. Dosage adjustment based on smoking behaviour would be of value in order to lower the incidence of non-therapeutic serum drug levels and, consequently, intoxication or inadequate antipsychotic response.

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