INPUT RATE-DEPENDENT STEREOSELECTIVE PHARMACOKINETICS - EXPERIMENTAL-EVIDENCE IN VERAPAMIL-INFUSED ISOLATED RAT LIVERS

The input rate dependency of verapamil (VER) kinetics was studied in s ingle-pass isolated rat livers perfused with a Krebs-bicarbonate buffe r solution, containing albumin and red blood cells, at a flow rate of 15 ml/min. Racemic VER was infused at a constant rate of similar to 50 (low dose, N = 5) or similar to 100 (high dose, N = 5) mu g/min throu gh the inlet catheter (portal vein). Inlet and outlet samples were tak en periodically over 90 min. Additionally, liver samples were obtained at the end of infusion. Perfusate and liver samples were analyzed usi ng a chiral liquid chromatographic method for determination of the ind ividual enantiomers of VER and its metabolites, norverapamil (NOR). Af ter the low-dose infusion, the hepatic availability of S-VER (0.102 +/ - 0.021) was greater than that of its antipode (0.071 +/- 0.020). A 2- fold increase in the input rate resulted in a significant increase in the hepatic availabilities of S-VER (0.195 +/- 0.040) and R-VER (0.182 +/- 0.048). However, the increase was more pronounced for R-VER, resu lting in a significant decrease in the S:R availability ratio from 1.4 7 +/- 0.20 (low dose) to 1.09 +/- 0.14 (high dose) and loss of stereos electivity at the high dose. The S:R ratio of NOR concentration was al so input rate-dependent. However, the degree of stereoselectivity for the outlet concentrations of NOR (S:R ratios of 2.42 +/- 0.42 and 1.88 +/- 0.20 for the low and high doses, respectively) was greater than t hat for the parent drug at both doses. These data provide direct exper imental evidence that input rate can affect the stereoselectivity in t he metabolism of racemic drugs.