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.
OBJECTIVE
This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects.


METHODS
Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of > or = 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-beta-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum gamma-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays.


RESULTS
VGB treatment had no influence on antipyrine clearance (28 +/- 5.6 vs. 30 +/- 4.5 ml/h/kg 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 concentration ratio (6.8 +/- 3.1 vs. 6.1 +/- 3.1) and serum gamma-glutamyltransferase activity (12 +/- 3 vs. 11 +/- 3 IU/L). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 +/- 3.2 vs. 13.9 +/- 3.2 h; AUC, 874 +/- 301 vs. 939 +/- 272 ng/ L/h) and levonorgestrel (half-life, 17.7 +/- 5.2 vs. 23.1 +/- 9.8 h; AUC, 27.5 +/- 9.6 vs. 30.0 +/- 12.0 micrograms/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment.


CONCLUSIONS
At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.
Bartoli
A
A
Clinical Pharmacology Unit, University of Pavia, Italy.
Gatti
G
G
Cipolla
G
G
Barzaghi
N
N
Veliz
G
G
Fattore
C
C
Mumford
J
J
Perucca
E
E
D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology; D000983:Antipyrine / Q000097:blood / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D003277:Contraceptives, Oral, Combined / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D045166:Estradiol Congeners / Q000097:blood / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D016912:Levonorgestrel / Q000097:blood / Q000493:pharmacokinetics*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism; D010919:Placebos; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000097:blood
D000927:Anticonvulsants; D003277:Contraceptives, Oral, Combined; D045166:Estradiol Congeners; D010919:Placebos; D004997:Ethinyl Estradiol; D005680:gamma-Aminobutyric Acid; D016912:Levonorgestrel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D005723:gamma-Glutamyltransferase; D020888:Vigabatrin; D000983:Antipyrine