Disposition of salmeterol xinafoate in laboratory animals and humans.
The disposition of [14C]salmeterol xinafoate, a new inhaled beta 2-adrenoceptor agonist with both bronchodilator and antiinflammatory activity, has been studied in laboratory animals and humans following intravenous and oral administration. [14C]Salmeterol was rapidly absorbed in animal species and humans with Cmax observed within 2 hr. Cmax was similar for normalized oral dose level in mice, rats, and rabbits. In dogs, Cmax was higher and reflected the greater oral bioavailability 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 salmeterol 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 distributed throughout body tissues in rats. The highest concentrations were 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. In all species the majority of an oral or intravenous dose (55-75%) was excreted in feces. Biliary excretion in rats and dogs accounted for 53% (0-27 hr) and 40% (0-8 hr) of an oral dose, respectively, indicating good absorption across the gastrointestinal tract. Enterohepatic circulation was significant in rats. Salmeterol was cleared predominantly by metabolism in animals and humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Manchee
G R
GR
Glaxo Group Research Ltd., Drug Metabolism III Department, Ware, Herts, UK.
Barrow
A
A
Kulkarni
S
S
Palmer
E
E
Oxford
J
J
Colthup
P V
PV
Maconochie
J G
JG
Tarbit
M H
MH
D000042:Absorption; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D001993:Bronchodilator Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068299:Salmeterol Xinafoate; D014018:Tissue Distribution
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D002250:Carbon Radioisotopes; D000068299:Salmeterol Xinafoate; D000420:Albuterol