Role of the Smoking-Induced Cytochrome P450 (CYP)1A2 and Polymorphic CYP2D6 in Steady-State Concentration of Olanzapine

Abstract

This study investigated whether the smokinginducible cytochrome P450 (CYP) 1A2 and the polymorphic CYP2D6 play significant roles in the metabolism of olanzapine and its clinical effects at steady-state treatment. Caffeine and debrisoquine were used as measures of CYP1A2 and CYP2D6, respectively. After drug therapy for 15 days, the effect of olanzapine on the activities of CYP1A2 and CYP2D6 was also examined. Seventeen psychiatric patients (9 men and 8 women) were orally administered olanzapine, at a mean +/- standard deviation (SD) dosage of 10 mg/d for all smokers (n = 8) and 7.5 +/- 2.5 mg/d (range, 5-10 mg) for nonsmokers (n = 9;p <0.01). The plasma concentration-to-dose (C:D) ratio was closely correlated to the CYP1A2 activity ( s = -0.89;p <0.0001). The mean urinary caffeine indexes of nonsmokers and smokers were 17 +/- 8 and 101 +/- 44, respectively, indicating that smoking had induced a sixfold higher CYP1A2 activity (p <0.0001). Likewise, the olanzapine plasma C:D ratio (ng.mL.mg) was about fivefold lower in smokers (7.9 +/- 2.6) than in nonsmokers (1.56 +/- 1.1;p <0.0001). On day 15 of the antipsychotic therapy, the percentage decrease in Brief Psychiatric Rating Scale (BPRS) total score relative to the predosing score (in the drug-free period) was higher for nonsmokers than for smokers (30.4 +/- 10% vs. 12.5 +/- 14%;p <0.01). Six nonsmokers and three smokers experienced side effects with olanzapine. After 15 days of drug treatment, olanzapine had caused significant (p <0.0001) and substantial CYP1A2 inhibition (by 50%) in comparison with predosing values, and such inhibition can contribute to adverse drug interactions. In conclusion, smoking-induced increased CYP1A2 activity significantly diminished plasma olanzapine concentrations and the antipsychotic effect of the drug. The performance of a simple caffeine test may assist in individualization of the olanzapine dosage.

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

“…16,[24][25][26][27][28][29][30][31][32] No effect of age, gender or other drugs was observed in our cohort. Previous reports are contradictory on these factors.…”

“…19 The CYP1A2*1F (À163A) polymorphism was associated with higher clearance of the CYP1A2 substrate caffeine in Caucasian smokers 18,19 but not in nonsmokers or in Korean smokers. Despite the close concordance between caffeine and olanzapine clearance, 26,36 different characteristics in the examined study populations-steady-state olanzapine concentrations in patients vs single-dose administration in healthy volunteers-may have led to different results.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…For example, the CYP2D6 phenotype did not correlate with the olanzapine AUC after a single dose or plasma concentrations at steady state (Carillo et al, 2003). CYP2D6 polymorphism is unlikely to be important for these compounds.…”

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

“…This has been shown for haloperidol (Jann et al, 1986) and tacrine (Zevin and Benowitz, 1999). Other examples are: fluvoxamine levels in smokers are 1/3 that of nonsmokers (Spigset et al, 1995), clozapine levels are 1/3 lower for men, 1/5 for women compared with nonsmokers (Haring et al, 1989), and smoker olanzapine levels are 1/5 that of nonsmokers (Carrillo et al, 2003). Clearly cessation of smoking can cause "overdose" toxicity for a patient taking any of these medications and then stops smoking.…”