Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2

Background and Objective: Oral contraceptives (OCs) can inhibit drug metabolism, but their effect on various cytochrome P450 (CYP) enzymes and drugs can be different. Our objective was to study the effect of combined OCs, containing ethinyl estradiol (INN, ethinylestradiol) and gestodene, on CYP1A2 activity, as well as their interaction potential with tizanidine. Methods: In a parallel-group study, 15 healthy women using OCs and 15 healthy women without OCs (control subjects) ingested a single dose of 4 mg tizanidine. Plasma and urine concentrations of tizanidine, as well as several of its metabolites (M-3, M-4, M-5, M-9, and M-10), and pharmacodynamic variables were measured until 24 hours after dosing. As a marker of CYP1A2 activity, an oral caffeine test was performed in both groups. Results: The mean area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of tizanidine was 3.9 times greater (P <.001) and the mean peak plasma tizanidine concentration (Cm) was 3.0 times higher (P <.001) in the OC users than in the control subjects. In 1 OC user the AUC(0-infinity) of tizanidine exceeded the mean AUC(0-infinity) of the control subjects by nearly 20 times. There were no significant differences in the elimination half-life or time to peak concentration in plasma of tizanidine between the groups. Tizanidine/metabolite ratios in plasma (M-3 and M-4) and urine (M-3, M-4, M-5, M-9, and M-10) were 2 to 10 times higher in the users of OCs than in the control subjects. In the OC group the excretion of unchanged tizanidine into urine was, on average, 3.8 times greater (P =.008) than in the control subjects. The plasma caffeine/paraxanthine ratio was 2.8 times higher (P < 001) in the OC users than in the control subjects. The caffeine/paraxanthine ratio correlated significantly with the AUC(0-infinity) and peak concentration of tizanidine in plasma, with its excretion into urine, and with, for example, the tizanidine/M-3 and tizanidine/M-4 area under the plasma concentration-time curve ratios. Both the systolic and diastolic blood pressures were lowered by tizanidine more in the OC users (-29 +/- 10 mm Hg and -21 8 mm Hg, respectively) than in the control subjects (- 17 +/- 9 mm Hg and - 13 +/- 5 mm Hg, respectively) (P < .01). Conclusions: OCs containing ethinyl estradiol and gestodene increase, to a clinically significant extent, the plasma concentrations and effects of tizanidine, probably mainly by inhibiting its CYP1A2-mediated presystemic metabolism. Care should be exercised when tizanidine is prescribed to OC users.