Pharmacokinetic analysis verifies P450 function during in vitro and in vivo application of a bioartificial liver.
Lidocaine is a sensitive substrate for evaluating liver P450 function. In this study, metabolism of lidocaine by xenogeneic hepatocytes in a hollow fiber, bioartificial liver was measured under in vitro conditions (n = 6) and in an anhepatic 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.
Nyberg
S L
SL
Department of Surgery, University of Minnesota, Minneapolis.
Mann
H J
HJ
Remmel
R P
RP
Hu
W S
WS
Cerra
F B
FB
D000818:Animals; D001187:Artificial Organs; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D015194:Diffusion Chambers, Culture; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology; D008012:Lidocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology*; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000502:physiology; D008297:Male; D010599:Pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous
D007527:Isoenzymes; C075860:3-hydroxylidocaine; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine