Pharmacogenetics in solid organ transplantation

Many pharmacogenomic predictors of drug response are now available, and include both drug metabolism-disposition factors and drug targets. It is well recognized that different transplant recipients respond in different ways to immunosuppressive medication (Zheng et al., 2005). The inter-individual variations are greater than the intra-individual variations, a finding consistent with the notion that inheritance is a determinant of drug responses. In the general population, it is estimated that genetics accounts for 20 to 95% of the variability in drug disposition and effects (Kalow et al., 1998). Many other non-genetic factors, such as organ function, drug interactions, and the nature of the disease, probably influence the effects of medication. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the inter-individual variability of the pharmacoki-netic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and immunologic risks. The promising role of pharma-cogenetics and pharmacogenomics in the effort to elucidate the inherited basis of differences between individual responses to drugs, lies in the potential ability to identify the right drug and dose for each patient. As an example, Mycophenolate mofetil (MMF) is an immunosuppressant widely used for the prophylaxis of organ rejection in renal, pancreas, and liver transplantation (Cai et al., 1998; Detry et al., 2003). It inhibits the inducible isoform of the enzyme inosine-monophosphate dehydrogenase (IMPDH II). IMPDH II is necessary for de novo purine synthesis in activated lymphocytes, whereas other cells generate purine nucleotides via the salvage pathway (Allison and Eugui, 2000). The use of MMF in liver transplantation (Detry et al., 2003), can be used to reduce the dosage of calcineurin inhibitors and steroids (Moreno et al., 2003). However, MMF administration may be associated with bone marrow and gastrointestinal toxicity, thus requiring therapeutic drug monitoring. The quantitation of gene transcription of the IMPDH inducible isoform using quantitative real-time PCR is feasible and reliable and may represent an important alternative to enzyme activity measurements based on liquid chromatographic methods. Therefore, the capability to discriminate between increased expressions of the inducible versus the constitutive isoform appears to be of critical importance. Moreover, a quantitative PCR assay may be used to analyze the drug target, thus reflecting MMF efficacy and tolerability, allowing a personalized immunosuppressive therapy.

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