Absolute oral bioavailability of traxoprodil in cytochrome P450 2D6 extensive and poor metabolisers.

Traxoprodil, a substituted 4-phenylpiperidine, is an N-methyl-D-aspartate (NMDA) receptor antagonist that is selective for receptors containing the NR2B subunit. In vivo and in vitro studies examining the disposition of traxoprodil have demonstrated that it is mainly metabolised by cytochrome P450 (CYP) 2D6, a major drug-metabolising enzyme that exhibits a genetic polymorphism. To assess the single-dose absolute oral bioavailability of traxoprodil in healthy male volunteers phenotyped as either CYP2D6 extensive or poor metabolisers. This was an open-label, three-way crossover study. Traxoprodil was administered as a single dose orally in solution of 50, 100 and 300mg and intravenously as a constant rate 2-hour infusion of 50 and 100mg. CYP2D6 phenotype was assigned following single-dose dextromethorphan administration. In poor metabolisers (n = 6), oral bioavailability was approximately 80% and was consistent with a liver extraction ratio of approximately 20% (plasma clearance of approximately 4 mL/min/kg) indicating near complete absorption. Following intravenous administration, the mean volume of distribution at steady state (V(ss)) was moderate (approximately 6.5 L/kg) and the mean elimination half-life (t((1/2))) was approximately 20 hours. Following oral administration the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) increased approximately proportionally with dose. In extensive metabolisers (n = 11), oral bioavailability was dose-dependent and nonlinear. At the 100mg dose, the absolute oral bioavailability was approximately 39.5%. Overall, the oral bioavailability ranged from 22.8% to 62.1% and its estimation was confounded by large differences in plasma concentrations at oral doses without equivalent intravenous doses. Following intravenous administration, plasma clearance was high (approximately 27 mL/min/kg), the V(ss) was moderate (approximately 4 L/Kg) and the t((1/2)) was approximately 2-4 hours. Following oral administration the C(max) and AUC(infinity) increased more than proportionally with dose. Apparent oral clearance decreased with increasing oral dose. However, t((1/2)) was approximately the same at all doses (approximately 4 hours). The pharmacokinetics of traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on traxoprodil pharmacokinetics is minimal.