Nonlinear pharmacokinetics of TAK-044, a new endothelin antagonist, in rats.
The mechanism of the nonlinear pharmacokinetics of TAK-044 in rats was shown from in vivo and in vitro studies to be due to capacity-limited hepatic uptake. In the rats, which were given intravenous injections of (14)C-labeled TAK-044 ([(14)C]TAK-044) (1, 3, 10, 30 and 100 mg/kg), the AUC(inf) per unit dose of unchanged compound increased remarkably. An analysis model indicated that the CL(tot), V(1) and k(12) values of TAK-044 decreased significantly with increasing dose, whereas the k(el) values remained constant over the doses examined. The uptake clearance of [(14)C]TAK-044 by several tissues was investigated by an integration plot at doses from 0.3 to 60 mg/kg. This study showed that the liver played the principal role in the removal of TAK-044 from the plasma, while hepatic uptake was capacity-limited at doses greater than 30 mg/kg. The hepatic uptake study using rat hepatocytes indicated that a carrier-mediated transport system contributed to the hepatic uptake of TAK-044, and this system had high affinity (K(m,in vitro); 8.4 micromol/L) with low capacity (V(max,in vitro); 86.3 pmol/mg protein/min). These results show that the saturation of hepatic uptake by the carrier-mediated transport system could explain the nonlinear pharmacokinetics of TAK-044 in rats.
Takeuchi
T
T
Drug Analysis and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., 2-17-85, Juso-Honmachi, Yodogawaku, Osaka 532-8686, Japan. Takeuchi_Toshiyuki@takeda.co.jp
Tagawa
Y
Y
Hagihara
K
K
Maeshiba
Y
Y
Yamashita
K
K
Tsukuda
R
R
Yoshimura
Y
Y
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017711:Nonlinear Dynamics; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D000963:Antimetabolites; D016232:Endothelins; D010456:Peptides, Cyclic; C088196:TAK 044