Influence of hepatic dysfunction on cyclosporine metabolism in the pig.
Cyclosporine (CyA) is eliminated from the body via biliary excretion at a rate directly proportional to bile production and the functional status of the liver. Previous reports demonstrated that disturbances in the hepatic excretory function with a rise in the plasma bilirubin level are positively correlated with high blood concentrations of CyA and CyA plus metabolites (CyA + M). Less information is available about the blood concentrations of the CyA parental substance or CyA metabolites in the case of liver dysfunction when there was no elevation of serum bilirubin content. To answer this question, we compared the pharmacokinetic profile of CyA in a cholestatic and in a ischemic model in pigs. Our results show that in pigs receiving a single dose of CyA after liver ischemia, the blood concentrations of CyA and CyA + M are significantly increased independently of the serum bilirubin concentration, probably through a slow down of CyA metabolism by impairment of cytochrome P450 III A.
Mentha
G
G
Laboratory of Experimental Surgery, Department of Surgery, University Hospital, Geneva, Switzerland.
Schopfer
C
C
Vadas
L
L
Belenger
J
J
Morel
P
P
Criado
F
F
Rohner
A
A
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001711:Biotransformation; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D008111:Liver Function Tests; D023421:Models, Animal; D011517:Prothrombin Time; D013552:Swine
D016572:Cyclosporine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin