DISPOSITION OF SALMETEROL XINAFOATE IN LABORATORY-ANIMALS AND HUMANS

The disposition of [C-14]salmeterol xinafoate, a new inhaled beta2-adr enoceptor agonist with both bronchodilator and antiinflammatory activi ty, has been studied in laboratory animals and humans following intrav enous and oral administration. [C-14]Salmeterol was rapidly absorbed i n animal species and humans with C(max) observed within 2 hr. C(max) w as similar for normalized oral dose level in mice, rats, and rabbits. In dogs, C(max) was higher and reflected the greater oral bioavailabil ity in this species. The plasma t1/2, after intravenous administration , was 5 hr in rats and 2 hr in dogs. The volume of distribution of sal meterol was significantly greater than total body water in both rats ( 40 liters/kg) and dogs (6 liters/kg) and indicated high tissue uptake of the compound. Plasma clearance was high in rats (95 ml/min/kg) and dogs (30 ml/min/kg). Radioactive drug-related material was widely dist ributed throughout body tissues in rats. The highest concentrations we re present in kidney, liver, gastrointestinal tract, pituitary, lung, heart, and bone marrow. Transfer of radioactive drug-related Material across the placental barrier or into milk, studied in rats, was low. I n all species the majority of an oral or intravenous dose (55-75%) was excreted in feces. Biliary excretion in rats and dogs accounted for 5 3% (0-27 hr) and 40% (0-8 hr) of an oral dose, respectively, indicatin g good absorption across the gastrointestinal tract. Enterohepatic cir culation was significant in rats. Salmeterol was cleared predominantly by metabolism in animals and humans. The major routes of metabolism w ere species-dependent, such that in mice, rats, and rabbits, glucuroni dation of parent compound was predominant, in dog phase I metabolism f ollowed by sulfation was the major route, and in humans aliphatic oxid ation was predominant.