Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppressive therapy following transplantation; however, immunosuppressive drug regimens consist of multiple medications with narrow therapeutic indices and substantial inter-patient variability. Despite intensive therapeutic monitoring, considerable time can elapse before the desired therapeutic concentration is achieved, which increases the risk of graft rejection or drug-related toxicities. In addition, maintaining therapeutic concentrations of CNIs does not prevent the development of toxicities, such as nephrotoxicity.
Pharmacogenomics can greatly benefit solid organ transplant recipients through individualized drug therapy; tacrolimus is a widely used CNI and a substrate of cytochrome P450 3A (CYP3A) metabolizing enzymes and the efflux transporter p-glycoprotein (PGP) encoded by the ATP-binding cassette subfamily B member 1(ABCB1) gene. This dissertation describes work conducted in order to examine the effect of genetic variability in the above mentioned genes on the pharmacokinetics of tacrolimus and their contribution to a predisposition to adverse events or drug interactions in the transplant population.
Our retrospective study investigating the effect of genetic polymorphisms on the risk of CNI-induced renal dysfunction identified a time-sensitive effect for the CYP3A5 expressor genotype, which predicts increased renal tubular CYP3A5 expression, in modifying the risk for renal dysfunction in liver transplant patients.
This dissertation also examines the hypothesis that local tissue levels of tacrolimus and/or its major metabolite may be an improved indicator of nephrotoxicity, and through development of a robust and sensitive liquid chromatography/ mass spectrometry (LC/MS) analytical method to co-determine tacrolimus and its major metabolite, 13-O-demethyl tacrolimus (13-ODMT), in rat kidney tissues, we identified a possible relationship between tacrolimus dose and the extent of metabolite accumulation in the kidneys of rats receiving tacrolimus intra-peritoneally, paving the way for examining this relationship in kidney transplant recipients with calcineurin inhibitor-induced nephrotoxicity (CNIT).
Overall, my research aims to identify biomarkers that might assist in early prediction of optimal tacrolimus starting and maintenance doses. Importantly, these studies provide the foundation for prospectively identifying patients at higher risk for adverse effects or drug interactions, with the ultimate goal of improving treatment outcome and quality of life for the transplant recipient receiving tacrolimus.