Pharmacogenomics of immunosuppressive drug metabolism

Publisher Website
Google Scholar
Abstract
The immunosuppressants are potent and toxic drugs with narrow therapeutic ranges. The pharmacokinetic variability of these drugs has made establishing appropriate dosing difficult. Currently, therapeutic drug monitoring is an important adjunct to achieving the precarious balance between efficacy and toxicity. However, pharmacogenomic analysis has the potential to improve dosing strategies. Several of the drugs in this category are metabolized through complex pathways, which have the potential to be affected by genetic traits. The current literature has addressed several genes and polymorphisms in relation to these drugs. Polymorphisms related to the coding of P-glycoprotein (coded by the MDR-1 gene) and cytochrome P450 3A enzymes have been the main focus of research. These gene products are involved in regulating the absorption and metabolism of the principal immunosuppessants. Two polymorphisms (C3435T and G2677[A/T]) of the MDR-1 gene have been shown to influence the bioavailability and toxicity of tacrolimus and cyclosporin. Phase I metabolism of these drugs has been shown to be affected by two polymorphisms (CYP3A5*1 and CYP3AP1*1), related to cytochrome P450 3A5 expression, rather than cytochrome P450 3A4. The current literature has shown disparity as to which are the most important polymorphisms affecting the metabolism of immunosuppressants. Although pharmacogenomics has the potential to allow improvements in devising optimal dosing regimes, it has not yet offered any definitive solutions to the problems of dosing, because the process of elucidating the complex influence of genetics on drug metabolism is only starting to be unravelled.