The pharmacogenetics of calcineurin inhibitors: one step closer toward individualized immunosuppression?

The immunosuppressive drugs cyclosporin (CsA) and tacrolimus (Tac) are widely used to prevent acute rejection following solid-organ transplantation. However, the clinical use of these agents is complicated by their many side effects, a narrow therapeutic index and highly variable pharmacokinetics. The variability in CsA and Tac disposition has been attributed to interindividual differences in the expression of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and 3A5, and in the expression of the drug transporter P-glycoprotein (encoded by the ABCB1 gene, formerly known as the multidrug resistance 1 gene). Variation in the expression of these genes could in turn be explained by several recently-identified single nucleotide polymorphisms (SNPs). Determination of these SNPs in (future) transplant recipients has the potential to identify individuals who are at risk of under-immunosuppression or the development of adverse drug reactions. Ultimately, genotyping for CYP3A and ABCB1 may lead to further individualization of immunosuppressive drug therapy for the transplanted patient.