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29 September 2008

The role of genetics and pharmacogenetic monitoring in transplantation

M. Masri

Ann Transplant 2008; 13(1): 35-35 :: ID: 880192

Abstract

Traditionally the ideal dose of a drug is established by constructing a dose response curve. In order to obtain such a curve the drug has to exert a measurable response. However, for the currently used immunosuppressive agents it is nearly impossible, as until now there is no measurable parameter that can be used to construct these curves. Therapeutic drug monitoring "bioavailability" has been utilized to overcome this problem. Many protocols are being used to monitor immunosuppressive drugs bioavailability, these includes blood trough levels, peak levels (C2), abbreviated area under the curve (AUC) and full AUC. The 12 hour AUC is considered to be the best representative of the drug bioavailability, however, it still does not reflect the immunological status of the patient and does not correlate with graft function. A significant problem in the use of bioavailability as an indicator of drug efficacy, is its inter and intra patient variation at the same dose. Bioavailability is dependent on many factors such as, absorption, metabolism and elimination; all of these are influenced by genetic factors. Lymphocyte drug level monitoring has been introduced as an alternative measure of bioavailability as it represents the actual drug concentration at its site of action. This approach is more predictive of the immunological status of the patients as the drug concentration in the lymphocyte is correlated with lymphocyte count. The promise of pharmacokinetics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. Genetic polymorphisms are implicated in the inter-individual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs. With the introduction of polymerase chain reaction (PCR) it is now possible to analyze the genetic factors contributing to drug bioavailability, drug response and to graft outcome. It is now possible to predict the bioavailability of immunosuppressive drugs, by determining gene polymorphism of the recipient oxidative enzyme, the drug efflux p-glycoprotein (PGP), the cytochrom (CYP) 450, CYP 3A4, CYP 3A5 and multiple drug resistance gene 1 (MDR-1). Pre-transplant genotyping for polymorphism in these genes have been instrumental for determining the dose of the immunosuppressive agent and in dose selection as well as dose adjustment, especially in African Americans on tacrolimus therapy. Additional genotyping for genes prescribing for the drug receptor, cytokines and for genes involved in the clotting cascade which are also contributors for cerebrovascular disease (collectively known as CVD) have also contributed to the prediction of both graft and patient survival rates. The compatibility of the donor recipient genotype for many of these genes is now more relevant than HLA matching. The commercial availability of gene micro array chips for all of the above mentioned genes has led to an expansion in the field of genotyping from the research laboratories to clinical diagnosis. The cost and time needed to perform genotyping for both donor and recipient is similar to HLA typing. Through genotyping we have identified an ethnic group of organ donor/ recipients who have a zero tolerance for cyclosporine therapy. These patients are currently receiving alternate therapy and have normal graft function.

Keywords: therapeutic drug monitoring, bioavailability, lymphocyte

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358