TY - JOUR T1 - The Pharmacokinetics of a Thiazole Benzenesulfonamide β<sub>3</sub>-Adrenergic Receptor Agonist and Its Analogs in Rats, Dogs, and Monkeys: Improving Oral Bioavailability JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 771 LP - 777 DO - 10.1124/dmd.30.7.771 VL - 30 IS - 7 AU - Ralph A. Stearns AU - Randy R. Miller AU - Wei Tang AU - Gloria Y. Kwei AU - Frank S. Tang AU - Robert J. Mathvink AU - Elizabeth M. Naylor AU - Dawn Chitty AU - Vincent J. Colandrea AU - Ann E. Weber AU - Adria E. Colletti AU - John R. Strauss AU - Carol Ann Keohane AU - William P. Feeney AU - Susan A. Iliff AU - Shuet-Hing Lee Chiu Y1 - 2002/07/01 UR - http://dmd.aspetjournals.org/content/30/7/771.abstract N2 - 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 (&lt;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 ER -