Kinetic study of the hepatobiliary transport of a new prostaglandin receptor agonist.

The pharmacokinetics of the hepatobiliary transport of an anionic drug, 7,8-dihydro-5-[(E)-[[a-(3-pyridyl)-benzylidene]aminooxy]ethyl]-1- naphthyloxy]acetic acid (ONO-1301), a new prostaglandin (PG) I2 receptor agonist, was investigated in rats. During intravenous infusion of this compound, the drug concentrations in arterial blood, hepatic vein and liver and the biliary excretion rate were measured at steady state. At a low infusion rate, 30% of the ONO-1301 was extracted by the liver during a single pass, and the main clearance organ was demonstrated to be the liver. The total clearance, Cltot; hepatic extraction ratio, EH; and liver-to-plasma concentration ratio, Kp values, decreased as the infusion rate increased. Considering the infusion rate-dependent decrease in all three parameters, saturation of hepatic uptake was suggested to be the cause of the nonlinear pharmacokinetics. To confirm this hypothesis, the time profiles of the plasma and liver concentrations of ONO-1301 after intravenous administration of various doses (0.01-25 mg/kg) were analyzed in vivo. The early-phase hepatic uptake clearance at lower doses (0.01-1 mg/kg) was 28 ml/min/kg, which is close to the hepatic plasma flow rate. The uptake clearance also was decreased at the higher doses. The uptake mechanism was investigated with isolated rat hepatocytes. Both Na(+)-dependent and -independent uptake were observed and these were inhibited by hypothermia and ATP depletors, which suggests that the uptake is via carrier-mediated active transport. The initial uptake velocity exhibited concentration dependence, and the kinetic parameters were as follows: Km, 15.6 microM (Na(+)-dependent) and 3.8 microM (Na(+)-independent); Vmax, 5.9 nmol/min/mg (Na(+)-dependent) and 4.8 nmol/min/mg (Na(+)-independent). With these in vitro transport parameters, the plasma unbound fraction and the hepatic plasma flow rate, the hepatic uptake clearance was calculated from a mathematical model. The calculation also indicated that the uptake was so rapid that it was limited by the plasma flow rate. It is concluded that the carrier-mediated active transport systems demonstrated in vitro are responsible for the nonlinear pharmacokinetics of ONO-1301.