PHARMACOKINETICS OF TIAGABINE, A GAMMA-AMINOBUTYRIC ACID-UPTAKE INHIBITOR, IN HEALTHY-SUBJECTS AFTER SINGLE AND MULTIPLE DOSES

Tiagabine (TGB) HCl, a new antiepileptic compound, is a potent and spe cific inhibitor of gamma-aminobutyric acid (GABA) uptake. In conjuncti on with three phase I studies, the pharmacokinetics of TGB were examin ed in 58 healthy male volunteers. Study I involved single increasing d oses (2-24 mg TGB HCl); study II involved doses of 2-10 mg given once daily for 5 days; study III explored one dose daily (6 or 12 mg) for 1 4 consecutive days. Plasma TGB concentrations were measured by high-pe rformance liquid chromatography (HPLC). Pharmacokinetic parameters wer e calculated by standard noncompartmental methods. Pharmacokinetic pro files were similar in all three studies and indicated that the process es of absorption and elimination of TGB were linear. The drug was rapi dly absorbed, and half-life (t1/2) averaged 5-8 h. The accumulation ra tio was fairly low: < 1.4 in most subjects. Secondary peaks in plasma concentration-time profiles suggested enterohepatic recycling. Lack of significant effects on antipyrine clearance indicated that TGB does n ot induce or inhibit hepatic microsomal enzyme systems.