Purpose: The hepatic extraction of a novel antiarrhythmic, RSD1070, was investigated to test the hypothesis that the poor bioavailability observed in rats is due to high hepatic metabolism.
Methods: The pharmacokinetics of RSD1070 was examined in rats (n=8) and its metabolism was investigated using pooled rat hepatic microsomes. The free fraction in plasma and microsomal matrices was determined by equilibrium dialysis. Hepatic extraction was predicted by scaling-up of the microsomal kinetic data using the well-stirred liver model.
Results: RSD1070 demonstrated tri-exponential decay following single iv bolus administration of a dose of 12 mg/kg. RSD1070 exhibited a rapid elimination, t1/2 of 25 +/- 8 min and a CL(tot) of 71 +/- 9 mL/min/kg. Renal clearance based on 24 h urinary recovery was determined to be insignificant (<< 1% of CL(tot)). A Michaelis-Menten model described the elimination of RSD1070 with a K(m) of 0.45 microg/mL and Vmax of 2.81 microg/min/mg microsomal protein. Taking the V(max)/K(m) ratio (CL(int)) as the basis for scaling, the data from the microsomal kinetic studies (75 mL/min/kg) closely approximated the apparent CL(tot). In the scale-up of the in vitro CL(int), plasma free fraction (1.5%) and microsomal free fraction (15%) were determined and incorporated into the well-stirred liver model.
Conclusion: RSD1070 is a high hepatic extraction compound (E = 0.94) with a predicted CL(h) value that accounted for the CL(tot) observed in rats.