Time response of cytochrome P450 1A2 activity on cessation of heavy smoking

Background and Objective: Cytochrome P450 (CYP) 1A2 activity is induced by cigarette smoking. Thus smoking cessation in patients while they are undergoing therapy with a CYP1A2 substrate such as theophylline or clozapine increases its concentrations and may cause adverse effects. Our objective was to determine the time course of CYP1A2 activity changes after smoking cessation in heavy smokers as the basis for dosing adaptation schemes. Methods: The study was conducted in 8 men and 4 women (all white) who smoked 20 cigarettes or more per day. Sudden smoking cessation was carried out after a 14-day run-in period. Subjects were phenotyped for CYP1A2 activity at 6, 4, and I day before smoking cessation and at 0, 1, 2, 3, 6, 8, 10, and 13 days thereafter by use of the paraxanthine-to-caffeine ratio in plasma 6 hours after a 148-mg caffeine test dose. A monoexponential decay of CYP1A2 activity to a residual value was fitted to the data by nonlinear regression analysis. Results: On cessation of smoking, initial caffeine clearance (estimated geometric means and 95% confidence intervals) decreased significantly (P < .01), by 36.1% (30.9%-42.2%), from 2.47 mL (.) min(-1) (.) kg(-1) body weight (2.03-3.00 mL (.) min(-1) (.) kg(-1) body weight) to a new steady state of 1.53 mL (.) min(-1) (.) kg(-1) body weight (1.24-1.89 mL (.) min(-1) (.) kg(-1) body weight). The apparent half-life of CYP1A2 activity decrease was 38.6 hours (27.4-54.4 hours). Conclusion: Doses of CYP1A2 substrates with a narrow therapeutic range should be decreased immediately on cessation of heavy smoking. As a rule of thumb, a stepwise daily dose reduction of approximately 10% until the fourth day after smoking cessation is proposed, which should be accompanied by therapeutic drug monitoring.