Pharmacokinetics and metabolism of vigabatrin following a single oral dose of [14C]vigabatrin in healthy male volunteers.
14C-labeled vigabatrin (50 microCi), an antiepileptic drug, was administered to six healthy male volunteers as a single oral dose containing 1500 mg of vigabatrin to determine the disposition profile of 14C and parent drug, and to investigate the metabolism of vigabatrin in humans. Vigabatrin was well tolerated by all subjects. There were no clinically important changes in any clinical laboratory parameter. Plasma concentration profiles of both 14C and vigabatrin exhibited biexponential decay. AUC, Cmax, Tmax, and terminal phase t1/2, for 14C were consistently greater than vigabatrin (248.2 vs. 176.0 micrograms-hr/ml; 48.8 vs. 42.8 micrograms/ml; 0.7 vs. 0.6 hr; and 9.5 vs. 7.7 hr, respectively). Mean renal clearance, oral clearance, and volume of distribution for 14C was consistently lower than vigabatrin (1.20 vs. 1.45 ml/min/kg; 1.26 vs. 1.77 ml/min/kg; and 1.01 vs. 1.18 liters/kg, respectively). The mean percentage of recovery of 14C in urine was higher than vigabatrin (95.4 vs. 82.0%). The mean percentage of recovery of 14C in feces was 1.0%. Concentration ratios of 14C showed that vigabatrin distributes into red blood cells at a concentration of 30-80% of that in plasma. The concentration of vigabatrin in saliva was approximately 10% of that in the plasma. The main radioactive component eliminated in the urine was vigabatrin. Two minor urinary metabolites (< 5% of total dose) of vigabatrin were detected using liquid scintillation counting of HPLC eluant fractions. One urinary metabolite was identified by thermospray-LC/MS as the lactam metabolite of vigabatrin.
Durham
S L
SL
Marion Merrell Dow, Inc. Cincinnati, OH 45215.
Hoke
J F
JF
Chen
T M
TM
D000284:Administration, Oral; D000328:Adult; D000614:Aminocaproates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D020888:Vigabatrin
D000614:Aminocaproates; D000927:Anticonvulsants; D020888:Vigabatrin