Pharmacokinetic Analysis Verifies P450 Function During In Vitro and In Vivo Application of a Bioartificial Liver

Abstract

Lidocaine is a sensitive substrate for evaluating liver P450 function. In this study, metabolism of lidocaine by xenogen-eic hepatocytes in a hollow fiber, bioartificial liver was measured under in vitro conditions (n=6) and in an anhepa-tic rabbit model. Animals in the treatment group (n=6) received hemoperfusion by a bioartificial liver that contained 100 million rat hepatocytes. Other anhepatic rabbits received no hemoperfusion (n=3) or a bioartificial liver with no cells (n=3). Lidocaine clearance was 7.0 ± 0.6 ml/min, and the half-life of lidocaine was 5.6 ± 0.8 hr under in vitro conditions. Conversion of lidocaine to 3-hydroxy-lidocaine was confirmed in vitro and accounted for 46% of lidocaine elimination in the hepatocyte bioartificial liver. During in vivo application of the bioartificial liver, pharmacokinetic parameters of lidocaine metabolism, including drug half-life and metabolite formation, were significantly improved in anhepatic rabbits. 3-Hydroxy-lidocaine profiles verified the activity of a P450 isozyme expressed preferentially by rat hepatocytes in the bioartificial liver. We conclude that hepatic P450 activity was provided by xenogeneic hepatocytes during in vitro and in vivo applications of a bioartificial liver.