%0 Journal Article %A Ralph A. Stearns %A Randy R. Miller %A Wei Tang %A Gloria Y. Kwei %A Frank S. Tang %A Robert J. Mathvink %A Elizabeth M. Naylor %A Dawn Chitty %A Vincent J. Colandrea %A Ann E. Weber %A Adria E. Colletti %A John R. Strauss %A Carol Ann Keohane %A William P. Feeney %A Susan A. Iliff %A Shuet-Hing Lee Chiu %T The Pharmacokinetics of a Thiazole Benzenesulfonamide β3-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability %D 2002 %R 10.1124/dmd.30.7.771 %J Drug Metabolism and Disposition %P 771-777 %V 30 %N 7 %X The pharmacokinetics and oral bioavailability of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide ( 1 ), a 3-pyridyl thiazole benzenesulfonamide β3-adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (∼30 ml/min/kg) than in dogs and monkeys (both ∼10 ml/min/kg), and oral bioavailability was 17, 27, and 4%, respectively. Since systemic clearance was 25 to 40% of hepatic blood flow in these species, hepatic extraction was expected to be low, and it was likely that oral bioavailability was limited either by absorption or a large first-pass effect in the gut. The absorption and excretion of3H-labeled 1 were investigated in rats, and only 28% of the administered radioactivity was orally absorbed. Subsequently, the hepatic extraction of 1 was evaluated in rats (30%) and monkeys (47%). The low oral bioavailability in rats could be explained completely by poor oral absorption and hepatic first-pass metabolism; in monkeys, oral absorption was either less than in rats or first-pass extraction in the gut was greater. In an attempt to increase oral exposure, the pharmacokinetics and oral bioavailability of two potential prodrugs of 1 , an N-ethyl [(R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide; 2 ] and a morpholine derivative [(R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)- phenyl]thiazol-2-yl]benzenesulfonamide; 3 ], were evaluated in monkeys. Conversion to 1 was low (<3%) with both derivatives, and neither entity was an effective prodrug, but the oral bioavailability of 3 (56%) compared with 1 (4%) was significantly improved. The hypothesis that the increased oral bioavailability of 3 was due to a reduction in hydrogen bonding sites in the molecule led to the design of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide ( 4 ), a 2-pyridyl β3-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/30/7/771.full.pdf