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)CTAK-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)CTAK-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.