Extracorporeal application of a gel-entrapment, bioartificial liver: demonstration of drug metabolism and other biochemical functions.
Metabolic activity of a gel-entrapment, hollow fiber, bioartificial liver was evaluated in vitro and during extracorporeal hemoperfusion in an anhepatic rabbit model. The bioartificial liver contained either 100 million rat hepatocytes (n = 12), fibroblasts (n = 3), or no cells (n = 7) during hemoperfusion of anhepatic rabbits. Eight other anhepatic rabbits were studied without hemoperfusion as anhepatic controls, and three sham rabbits served as normal controls. Albumin production rates (mean +/- SEM) were similar during in vitro (17.0 +/- 2.8 micrograms/h) and extracorporeal (18.0 +/- 4.0 micrograms/h) application of the hepatocyte bioartificial liver. Exogenous glucose requirements were reduced (p < 0.01) and euglycemia was prolonged (p < 0.001) in anhepatic rabbits treated with the hepatocyte bioartificial liver. The maximum rate of glucose production by the hepatocyte bioartificial liver ranged from 50-80 micrograms/h. Plasma concentrations of aromatic amino acids, proline, alanine, and ammonia were normalized in anhepatic rabbits during hepatocyte hemoperfusion. Gel-entrapped hepatocytes in the bioartifical liver performed sulfation and glucuronidation of 4-methylumbelliferone. P450 activity was demonstrated during both in vitro and extracorporeal application of the BAL device by the formation of 3-hydroxy-lidocaine, the major metabolite of lidocaine biotransformation by gel-entrapped rat hepatocytes. In summary, a gel-entrapment, bioartificial liver performed multiple hepatocyte-specific functions without adverse side effects during extracorporeal application in an anhepatic, small animal model. With its potential for short term support of acute liver failure, scale-up of the current bioartificial liver device is indicated for further investigations in large animal, preclinical trials.
Nyberg
S L
SL
Department of Surgery, University of Minnesota, Minneapolis 55455.
Shirabe
K
K
Peshwa
M V
MV
Sielaff
T D
TD
Crotty
P L
PL
Mann
H J
HJ
Remmel
R P
RP
Payne
W D
WD
Hu
W S
WS
Cerra
F B
FB
D000418:Albumins / Q000096:biosynthesis; D000596:Amino Acids / Q000097:blood; D000818:Animals; D001187:Artificial Organs; D001711:Biotransformation; D001772:Blood Cell Count; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen; D004867:Equipment Design; D005112:Extracorporeal Circulation; D005782:Gels; D006464:Hemoperfusion; D006498:Hepatectomy; D006923:Hymecromone / Q000493:pharmacokinetics; D008012:Lidocaine / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000097:blood
D000418:Albumins; D000596:Amino Acids; D001786:Blood Glucose; D005782:Gels; D006923:Hymecromone; D014508:Urea; D003094:Collagen; D008012:Lidocaine