Effect of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Calcineurin Inhibitors: Part II

• Published in: Clinical pharmacokinetics 2010-04, Vol.49 (4), p.207-221
• Main Authors: Staatz, Christine E., Goodman, Lucy K., Tett, Susan E.
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Calcineurin; Calcineurin Inhibitors; Cyclosporine - adverse effects; Cyclosporine - pharmacokinetics; Cyclosporine - pharmacology; Cytochrome P-450 CYP3A - genetics; Drug Interactions; Drugs; General pharmacology; Genetic aspects; Genotype; Graft Rejection - genetics; Health aspects; Humans; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Organ Transplantation; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Polymorphism, Single Nucleotide; Review Article; Single nucleotide polymorphisms; Tacrolimus - adverse effects; Tacrolimus - pharmacokinetics; Tacrolimus - pharmacology
• ISSN: 0312-5963; 1179-1926
• DOI: 10.2165/11317550-000000000-00000

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes — in particular, CYP3A4 and CYP3A5 — and are transported out of cells via P-glycoprotein ( ABCB1 ). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 —392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1 128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 —392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited. For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time. This SNP has no clear association with acute rejection during ciclosporin therapy. Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression. This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation. The effect of the CYP3A5 6986A>G SNP on ciclosporin-and tacrolimus-related nephrotoxicity and development of hypertension is unclear. Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity. In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity. Studies with low patient numbers may account for many inconsistent results to date. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be