The primary goal of this project is to improve the management and survival of patients undergoing orthotopic liver transplantation (OLT) through an improved understanding of their drug disposition and dosing.
The specific aims are to gain an understanding of each of the following processes in OLT patients; absorption, by determining the time course of improvement of absorption for lipid soluble drugs and the means by which absorption can be enhanced; distribution, by measuring changes in drug-binding proteins over time and through measurements of actual amounts of bound and unbound drugs and metabolites; metabolism, by measuring the liver's ability to degrade low, high, and intermediate clearance drugs, to convert drugs to active moieties, and to alter availability of drugs passing through the liver after absorption; and elimination, by measuring the renal excretion of model compounds and therapeutic agents that characterize glomerular filtration and tubular secretion of drugs. Specific ABSORPTION studies will measure the effects of exogenous bile salts on cyclosporine (CyA) absorption. Drug DISTRIBUTION studies in OLT patients will measure the time course of changes in lipoprotein fractions, will quantitate the protein binding of CyA and its metabolites, and will determine the protein binding of highly-bound drugs in patients receiving those agents. Investigations of drug METABOLISM in OLT patients will profile Cya metabolites in blood, will examine the interconversion of prednisolone and prednisone, will determine the kinetics of azathioprine, will assess the effects of rejection on the hepatic transformation of antipyrine, and will quantitate the kinetics of a high clearance drug meperidine. The renal ELIMINATION studies in OLT patients will examine glomerular filtration through the use of inulin and the kinetics of gentamicin, and will examine tubular secretion using the model compound para-aminohippuric acid. This comprehensive investigation will not only determine the mechanisms behind altered drug disposition in OLT patients, but will also obtain that information in a manner that will provide clinically useful information.
