Abstract

Plasma concentration-time curves and urinary excretion of individual enantiomers of unchanged S-8666 and its N-monodemethylated metabolite, M-1, in male cynomolgus monkeys were measured after oral administration of racemic S-8666 at doses of 5, 10, and 50 mg/kg and also after intravenous injection at doses of 1, 5, and 10 mg/kg. The Tmax values for individual enantiomers of S-8666 in fasted male monkeys were 30 min after oral administration. The AUC values for S(-)-S-8666 were greater than those for R(+)-S-8666 and oral dose-AUC relationships of both enantiomers showed a linearity over the dose range used. Most of the S-8666 and a trace of M-1 were excreted in the first 24-hr urine, with no evidence of stereoselectivity from the amounts excreted. Since large portions were recovered from the urine as unchanged S-8666 after intravenous injection, most excretion occurs via the kidney. The t1/2 beta values and the Vdss for S(-)-S-8666 after intravenous injection were smaller than those for R(+)-S-8666. The CLt and the CLr values decreased with increasing intravenous doses, indicating saturation at a renal excretion process at high plasma concentrations of S-8666. The CLt and CLr values for R(+)-S-8666 were greater than those for the S(-)-enantiomer. The unbound fraction of R(+)-S-8666 in plasma was significantly greater than that of S(-)-S-8666 [21.6% for R(+), 12.0% for S(-)]. Renal clearance for the unbound fraction of S(-)-S-8666 was greater than that of R(+)-S-8666, suggesting stereoselective renal tubular secretion.