Intestinal absorption and presystemic elimination of the prokinetic agent, EM574, in the rabbit

The purpose of this study was to characterize the pharmacokinetics and dose proportionality of the prokinetic macrolide, EM574, in rabbits following intravenous dosing, and to determine the intestinal absorption and intestinal and hepatic first-pass elimination of EM574 in rabbits. Two doses (0.05 and 0.25 mg/kg) of EM574 were given to rabbits intravenously in a crossover study. In a separate gut perfusion study, rabbit duodenal or jejunal segments were perfused with EM574 solution at 0.2 mL/min for 130 min. Plasma levels of EM574 were determined by a validated LC-MS/MS assay, and concentrations in perfusate were determined by HPLC with UV detection. The absorptive clearance (PeA) of EM574 was calculated from the steady-state rate of disappearance from the gut lumen during perfusion. The cumulative amount (A(app)) of drug appearing in the systemic circulation was calculated by deconvolution, where the input response was the plasma concentration-time profile during intestinal perfusion and the unit impulse response was the mean profile following intravenous bolus dosing to sham-operated rabbits in a separate experiment. F(g)F(h) was calculated from the ratio of A(app) to the total amount disappeared from gut lumen during perfusion. Hepatic first-pass elimination was measured by intraportal venous infusion. EM574 exhibits linear kinetics over the dose range studied. CL, V(ss), and terminal half-life (mean +/- SD) of EM574 were 68.6 +/- 15.5 mL/min/kg, 13.4 +/- 3.0 L/kg, and 2.7 +/- 0.8 h, respectively. EM574 is expected to be absorbed completely from the rabbit small intestine based on its high jejunal PeA values (8.1 +/- 2.2, and 5.5 +/- 1.5 microL/min/cm following low and high dose perfusion, respectively). The first-pass extraction of EM574 was substantial and dose independent. Mean F(g) and F(h) were 0.14 and 0.20, respectively, suggesting that the intestinal and hepatic first-pass elimination of EM574 were comparable. Deconvolution was successfully applied in the determination of gut wall and hepatic first-pass elimination of EM574.