Many immunosuppressive drugs are characterised by a narrow therapeutic index. That is, the difference between a therapeutic dose and a toxic dose is small, often requiring patients on immunosuppressive regimes to have their drug dosage adjusted according to actual levels detected in the blood. This is complicated by the fact that individuals differ significantly their bioavailability, i.e. the fraction of a fixed administered dose of drug that reaches systemic circulation. This variability in drug response has been shown to have a heritable genetic component.
One main goal of immunosuppressive regimes has been to individualize drug therapy so as to optimise the balance between efficacy and drug related toxicity. Immunosuppressive drug regimes used in solid organ transplantation include the calcineurin inhibitors (CNI) cyclosporine A and tacrolimus as well as sirolimus. An ability to undertake pre-transplant tailoring of the CNI doses could both reduce the time where the drug is ineffective thus reducing the risk of rejection, as well as avoid a nephrotoxic dose which could reduce kidney function.
Immunosuppressive drugs are transported across the cellular membrane by the transmembrane pump P-glycoprotein, where they are metabolised by Cytochrome P450 (CYP) enzymes, a large diverse group of enzymes which account to more than 75% of all drug metabolism. Polymorphisms in the genes for Cytochrome P450 enzymes have been associated with differences in immunosuppressive drug metabolism, particularly metabolism of tacrolimus.
The majority of Cytochrome P450 drug metabolic activity is accounted for by the CYP3A sub family. The genes encoding the CYP3A sub family are located on chromosome 7. The main isoforms encoded are CYP3A4 and CYP3A5. Both isoforms carry a number of single nucleotide polymorphisms (SNPs) resulting in a number of alleles. CYP3A4 polymorphisms include CYP3A4*1 and CYP3A4*1B. CYP3A5 polymorphisms include CYP3A5*1 and CYP3A5*3. Most studies have demonstrated that patients with the CYP3A5*3 allelic variant show higher blood concentrations of tacrolimus therefore allowing lower maintenance doses of the immunosuppressant compared with patients with the CYP3A5*1 allele. In one study, the CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes were significantly more frequently associated with the development of biopsy-proven calcineurin related nephrotoxicity compared to the CYP3A4*1/CYP3A5*3 genotype.
Whilst therapeutic drug monitoring remains the primary method of individualizing immunosuppressive drug regimes, an understanding of the genetics and polymorphisms behind differing rates of drug metabolism may allow for prediction of potential drug responses allowing tailoring of dose before the treatment starts.
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