Liver transplantation is a life saving procedure that has been successfully performed on several hundred patients with terminal liver disease. It is considered as a therapeutic option for biliary atresia, primary biliary cirrhosis and certain metabolic disorders such as Alpha1-antitrypsin deficiency. The primary objective of this project is to determine the functional ability of the transplanted liver in terms of drug dispositional parameters. The ultimate objective of the proposal is to obtain sufficient background information to optimize drug therapy in orthotopic liver transplant (OLT) recipients. A fundamental understanding of the kinetics of different drugs, in particular, the immunosuppressants cyclosporine and prednisolone is vital to the optimization of drug therapy in this patient population.
The specific aims of the proposal are to determine the pharmacokinetics and bioavailability of cyclosporine, prednisolone and vitamin E; to determine the disposition kinetics of antipyrine and acetaminophen and to determine the in vitro time course of changes in drug protein binding in OLT recipients. Cyclosporine and prednisolone kinetics and bioavailability studies will be carried out in adults and children at two and five weeks post-transplant. Vitamin E kinetics will be determined in pediatric OLT patients prior to and after orthotopic liver transplantation. Antipyrine and acetaminophen kinetics will be determined in adult OLT patients prior to and after transplant under stable conditions. An evaluation of the different kinetic parameters, such as half life and clearance, will provide information on the efficiency with which the new liver metabolizes these drugs. The study design for cyclosporine and prednisolone will provide an estimation of time dependent changes in different kinetic parameters for these drugs. Information on the role of bile salts on the absorption and the effect of liver disease on the disposition of cyclosporine will also be evaluated. Studies on antipyrine and acetaminophen will provide a functional assessment of the oxidative and conjugating drug metabolizing enzyme systems in the transplanted liver. Drug protein binding studies will be carried out in vitro, using blood obtained from adult OLT patients, once a week for 6 weeks. This will provide information on the ability of the transplanted liver to synthesize plasma proteins and on its functional capacity in eliminating endogenous drug binding inhibitors.
