PHARMACOKINETICS AND PLASMA-PROTEIN BINDING OF TAMSULOSIN HYDROCHLORIDE IN RATS, DOGS, AND HUMANS

The pharmacokinetics of tamsulosin hydrochloride, a selective alpha(1) -adrenoceptor antagonist, was investigated after single iv and oral do sing to rats and dogs, and oral dosing to healthy male volunteers. Aft er 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 (CLB) 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 maximu m levels within 1 hr in rats and dogs, and at 1.0-1.8 hr in humans. Va lues for oral clearance (CLoral) in rats, dogs, and humans were 34.5-1 13.6, 3.01-3.99, and 0.031-0.041 l/hr/kg, respectively, showing wide v ariation among these species. The absolute bioavailability (F) increas ed 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 0.33 mg/kg dose range ). The plasma protein binding of C-14-tamsulosin in humans was much hi gher (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) va lue in rats, dogs, and humans decreased in this order (1.2, 0.72, and 0.53, respectively), corresponding to the decrease in plasma unbound f raction (fu) in these species. These results imply that the large inte rspecies difference in CLoral is attributable to a difference not only in hepatic metabolism but also in protein binding among these species .