Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys.
1. The pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor, were investigated in rats and monkeys. After oral administration, KW-4490 was rapidly absorbed, and then its plasma concentrations apparently declined with half-lives of approximately 5 h in rats and 3.5 h in cynomolgus monkeys; however, a number of secondary peaks were apparent in the profiles for both species. The plasma pharmacokinetics of KW-4490 were comparable between rats and monkeys. 2. After oral administration, KW-4490 was mainly eliminated by metabolism to acylglucuronides and renal excretion in the unchanged form. KW-4490 acylglucuronides were found in monkey but not rat urine. In rats, KW-4490 acylglucuronides were excreted only in bile. Although the pathway of excretion of acylglucuronides differed between rats and monkeys, cumulative excretion in the two animals was very similar, as expected from comparable hepatic clearance for glucuronidation in rat and monkey liver microsomes. 3. The glomerular filtration rate of unbound KW-4490 indicated that renal tubular secretion was significant in monkeys, whereas reabsorption was significant in rats. These species differences in urinary excretion of KW-4490 and its acylglucuronide metabolites are most likely due to substrate specificity of active transporters in rat and monkey kidney.
Fujita
K
K
Pharmacokinetic Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd, Shizuoka, Japan. kazuhiro.fujita@kyowa.co.jp
Kodaira
H
H
Kuwabara
T
T
Kobayashi
H
H
D000818:Animals; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004146:Dioxanes / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D001798:Blood Proteins; D003509:Cyclohexanecarboxylic Acids; D004146:Dioxanes; D020719:Glucuronides; C530154:KW 4490; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors