Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: Contribution of intestinal first-pass effect to low bioavailability in rats.
The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.
Chung
Hye J
HJ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Choi
Young H
YH
Choi
Hye D
HD
Jang
Ji M
JM
Shim
Hyun J
HJ
Yoo
Moohi
M
Kwon
Jong W
JW
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D004285:Dogs; D004355:Drug Stability; D004912:Erythrocytes / Q000378:metabolism; D005419:Flavonoids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007420:Intestine, Large / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; D005419:Flavonoids; C121889:recoflavone