Hepatic clearance of gitoxin: pharmacokinetic study on rabbit isolated liver. Influence of protein binding and comparison with digoxin

Abstract

Hepatic clearance of gitoxin has been studied in the rabbit and compared with that of digoxin using an isolated perfused liver technique. During 1.5 hour perfusions with a modified Krebs-Henseleit solution, gitoxin perfusate levels decreased biexponentially; the distribution and elimination half-lives were estimated to be 0.14 and 1.25 hour, Vd area to be 95.5 ml.g-1 and intrinsic metabolic clearance to be 1.98 ml.min-1.g-1. During 1.5 hour perfusions with modified Krebs-Henseleit solution containing 2.7% bovine serum albumin, gitoxin perfusate levels decreased monoexponentially. This is probably due to protein binding which moderates hepatic uptake so that distribution is not yet complete after 1.5 hour and it is therefore impossible to discriminate the two phases. This was confirmed by 5 hour perfusion experiments with an emulsion of perfluorocarbon in the modified Krebs-Henseleit solution also containing 2.7% bovine serum albumin, during which gitoxin levels decreased biexponentially. Distribution and elimination half-lives have been estimated to be 0.31 and 5.54 hours, Vd area to be 139 ml.g-1 and intrinsic metabolic clearance to be 1.36 ml.min-1.g-1. Gitoxin has been compared in these experimental conditions with digoxin, one of the most often used cardiotonic's. Distribution and elimination half-lives of digoxin were estimated to be 0.34 and 4.52 hours, Vd area to be 46.5 ml.g-1 and intrinsic metabolic clearance to be 0.17 ml.min-1.g-1. Other pharmacokinetic parameters (alpha, beta, V1, V2...) also have been calculated for these three types of perfusion experiments.