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In vitro-in vivo investigation of the hepatic extraction of RSD1070: a novel antiarrhythmic compound Tong, Vincent Wai-Yip


Purpose. The hepatic extraction of a novel antiarrhythmic, RSD1070, was investigated to test the hypothesis that its 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 parent compound disappearance studies in pooled rat hepatic microsome incubations. The free fraction in plasma and microsomal matrices was determined by equilibrium dialysis. Hepatic extraction was predicted from the scaling-up of the microsomal kinetic data using the well-stirred liver model. Results. RSD1070 pharmacokinetics demonstrated a three-compartment model following single iv bolus administration of a dose of 12 mg/kg. RSD1070 exhibited a rapid elimination t1/2 (25 ± 8 min) and a CLtot of 71 ± 9 mL/min/kg. Renal clearance based on 24-hour urinary recovery was determined to be insignificant ( « 1% of CLtot). A Michaelis-Menten model described the consumption of RSD1070 with a Km of 0.45 μg/mL and Vmax of 2.81 μg/min/mg microsomal protein. The in vitro half-life approach examined the first-order consumption rate of RSD1070 (1 μM) in microsomal incubation. Taking the Vmax/Km ratio (CLint) and the in vitro t1/2 as the basis for scaling, the data from the microsomal kinetic studies (75 mL/min/kg) closely approximated the apparent CLtot. Required for the scale-up of in vitro CLint, 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 in vitro CLh value that accounted for the CLtot observed in rats. [Scientific formulae used in this abstract could not be reproduced.]

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