A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY ON THE EFFECT OF VIGABATRIN ON IN-VIVO PARAMETERS OF HEPATIC-MICROSOMAL ENZYME-INDUCTION AND ON THE KINETICS OF STEROID ORAL-CONTRACEPTIVES IN HEALTHY FEMALE VOLUNTEERS

Purpose: This study was conducted to determine whether vigabatrin affe cts in vivo indices of hepatic microsomal enzyme activity and the phar macokinetics of steroid oral contraceptives in healthy subjects. Metho ds: Under double-blind conditions, 13 female healthy volunteers receiv ed, in random order and with a washout interval of greater than or equ al to 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maint enance dosage, 3,000 mg daily) and placebo, respectively. The clearanc e and half-life of antipyrine (a broad marker of drug oxidation capaci ty), the urinary excretion of 6-beta-hydroxycortisol (a selective mark er of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma-glutamyltransferase (a nonspecific index of microsomal enzyme ac tivity) were determined after 3 weeks of each treatment. The single-do se kinetics of a combined oral contraceptive containing 30 mu g ethiny l estradiol and 150 mu g levonorgestrel were also determined after 3 w eeks of treatment by specific radioimmunologic assays. Results: VGB tr eatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/ - 4.5 mlihikg on placebo), antipyrine half-life (15.5 +/- 3.5 vs. 14.1 +/- 2.1 h), urinary 6-beta-hydroxycortisol excretion (488 +/- 164 vs. 470 +/- 228 nmol/ day), 6-beta-hydroxycortisol-to-cortisol concentrat ion ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransf erase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmaco kinetic parameters between VGB and placebo sessions were found for eth invl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUG, 874 /- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrll (half-life, 17.7 +/ - 5.2 vs. 23.1 +/- 9.8 h; AUG, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 mu g/L/h ). Two subjects, however, showed a 50 and a 39% reduction in ethinyl e stradiol AUC during VGB treatment. Conclnsions: At therapeutic dosages , VGB did not modify in vive indices of hepatic microsomal enzyme acti vity and did not interfere significantly with the CYP3Amediated metabo lism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contr aceptives or interact pharmacokinetically with drugs that are eliminat ed mainly by oxidative pathways, particularly those involving cytochro me CYP3A.