Input rate-dependent stereoselective pharmacokinetics. Experimental evidence in verapamil-infused isolated rat livers

The input rate dependency of verapamil (VER) kinetics was studied in single-pass isolated rat livers perfused with a Krebs-bicarbonate buffer solution, containing albumin and red blood cells, at a flow rate of 15 ml/min. Racemic VER was infused at a constant rate of approximately 50 (low dose, N = 5) or approximately 100 (high dose, N = 5) micrograms/min through the inlet catheter (portal vein). Inlet and outlet samples were taken periodically over 90 min. Additionally, liver samples were obtained at the end of infusion. Perfusate and liver samples were analyzed using a chiral liquid chromatographic method for determination of the individual enantiomers of VER and its metabolites, norverapamil (NOR). After 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, resulting in a significant decrease in the S:R availability ratio from 1.47 +/- 0.20 (low dose) to 1.09 +/- 0.14 (high dose) and loss of stereoselectivity at the high dose. The S:R ratio of NOR concentration was also input rate-dependent. However, the degree of stereoselectivity for the outlet concentrations of NOR (S:R ratios 2.42 +/- 0.42 and 1.88 +/- 0.20 for the low and high doses, respectively) was greater than that for the parent drug at both doses.(ABSTRACT TRUNCATED AT 250 WORDS)