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 specific inhibitor of gamma-aminobutyric acid (GABA) uptake. In conjunction with three phase I studies, the pharmacokinetics of TGB were examined in 58 healthy male volunteers. Study I involved single increasing doses (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 14 consecutive days. Plasma TGB concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by standard noncompartmental methods. Pharmacokinetic profiles were similar in all three studies and indicated that the processes of absorption and elimination of TGB were linear. The drug was rapidly absorbed, and half-life (t1/2) averaged 5-8 h. The accumulation ratio 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 not induce or inhibit hepatic microsomal enzyme systems.