CYP3A polymorphisms and immunosuppressive drugs in solid-organ transplantation.
Most immunosuppressive drugs have a narrow therapeutic index and large interpatient variabilities in their pharmacokinetic and pharmacodynamic profiles. Identification of functional single-nucleotide polymorphisms in genes encoding for drug metabolizing enzymes has great potential to improve the drug efficacy and safety profiles, since these genetic factors may be important biomarkers for individualization of immunosuppressive therapy. This article summarizes current knowledge regarding the impact of CYP3A polymorphisms on immunosuppressive drug pharmacokinetics. Many retrospective studies have shown a clear relationship between CYP3A5*1/*3 polymorphism and tacrolimus pharmacokinetics, while the influence of CYP3A5*1/*3 or CYP3A4*/*1B on ciclosporin and sirolimus exposure are still questionable. CYP3A polymorphisms may partially contribute to the clinical variability of the enzyme-mediated drug interactions. Drug-drug interactions may also influence the phenotypic consequence of CYP3A polymorphisms. Population pharmacodynamic/kinetic/genomic modeling was proposed as an emerging and promising approach to quantitatively explore the contribution of genetic polymorphisms to the large interpatient variability in the pharmacokinetic and pharmacodynamic profiles of immunosuppressive drugs. Prospective, randomized studies in large patient populations are needed to further clarify the genetic effects of CYP3A on immunosuppressive drug exposure and response.
Office of Clinical Pharmacology, Center for Drug Research and Evaluation, The US FDA, Silver Spring, MD 20993, USA. jian.wang@fda.hhs.gov
Jian
J
Wang
D000935:Antifungal Agents / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004347:Drug Interactions; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016377:Organ Transplantation / Q000592:standards*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012449:Safety; D016559:Tacrolimus / Q000627:therapeutic use
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus