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Indexed/Abstracted in: EMBASE, Science Citation Index Expanded (SciSearch), Scopus
Impact Factor 0,246
Macphee I. A. M. 1, Fredericks S. 2, Holt D. W. 2
1 Cellular and Molecular Medicine, Renal Medicine, St. George’s Hospital Medical School, London, UK;
2 Cardiac and Vascular Sciences Analytical Unit, St. George’s Hospital Medical School, London, UK
The drugs used to prevent the rejection of organ transplants by suppressing the immune response (immunosuppressive drugs) are both potent and toxic resulting in a narrow therapeutic index. They can be described as “critical dose drugs”. Use of these drugs is rendered more difficult by marked interindividual variation in the dose of drug required to achieve target blood concentrations, probably based on differences in the intestinal barrier to drug absorption. The most marked differences were initially identified between ethnic groups, with Black patients requiring much higher doses of the calcineurin inhibitors and sirolimus than other ethnic groups. Clearly, ethnicity is a crude surrogate for genotype and single nucleotide polymorphisms have been identified for several genes that predict the oral bioavailability of the immunosuppressive drugs. This review will focus on genetic influences on the enzymes in the cytochrome P4503A family (CYP3A4 and CYP3A5) that metabolise most of the immunosuppressive drugs and the MDR-1 gene that encodes the drug efflux pump P-glycoprotein. These proteins act in concert in the enterocyte to form a barrier to drug absorption. CYP3A4 and CYP3A5 in the liver are responsible for the metabolism prior to clearance of most of the immunosuppressive drugs. In addition to determining the blood concentration of drugs, these genetic differences, in particular for MDR-1 may also have a significant effect on pharmacodynamics. Genotyping at these single nucleotide polymorphisms is technically straightforward and inexpensive. Use of a pharmacogenetic approach to individualise the prescribing of the immunosuppressive drugs has the potential to reduce both treatment-failure and toxicity, with improved patient outcomes.