Abstract

The pharmacokinetics of tamsulosin hydrochloride, a selective α₁-adrenoceptor antagonist, was investigated after single iv and oral dosing to rats and dogs, and oral dosing to healthy male volunteers. After iv dosing, plasma tamsulosin concentrations declined in an apparent biexponential manner with terminal half-lives of 0.32 hr in rats and 1.13 hr in dogs. Values for total blood clearance (CL_B) were 6.57 l/hr/kg in rats and 1.61 l/hr/kg in dogs, suggesting “hepatic blood flow-limited” and “intermediate flow-dependent” clearance, respectively. After oral dosing, tamsulosin was rapidly absorbed and reached maximum levels within 1 hr in rats and dogs, and at 1.0–1.8 hr in humans. Values for oral clearance (CL_oral) in rats, dogs, and humans were 34.5–113.6, 3.01–3.99, and 0.031–0.041 l/hr/kg, respectively, showing wide variation among these species. The absolute bioavailability (F) increased with dose in rats (from 6.9% at 1 mg/kg to 22.8% at 10 mg/kg), but was almost constant in dogs (29.7–42.0% over the 0.3–3 mg/kg dose range). The plasma protein binding of¹⁴C-tamsulosin in humans was much higher (98.9–99.1%) than that in rats and dogs (79.0–80.6% and 90.2–90.3%, respectively). The ratio of blood to plasma concentrations (R_B) value in rats, dogs, and humans decreased in this order (1.2, 0.72, and 0.53, respectively), corresponding to the decrease in plasma unbound fraction (fu) in these species. These results imply that the large interspecies difference in CL_oral is attributable to a difference not only in hepatic metabolism but also in protein binding among these species.