Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I

Staatz, Christine E., Goodman, Lucy K. and Tett, Susan E. (2010) Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clinical Pharmacokinetics, 49 3: 141-175. doi:10.2165/11317350-000000000-00000


Author Staatz, Christine E.
Goodman, Lucy K.
Tett, Susan E.
Title Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I
Journal name Clinical Pharmacokinetics   Check publisher's open access policy
ISSN 0312-5963
1179-1926
Publication date 2010
Year available 2010
Sub-type Article (original research)
DOI 10.2165/11317350-000000000-00000
Volume 49
Issue 3
Start page 141
End page 175
Total pages 35
Editor A. Prakash
Place of publication Aukland, New Zealand
Publisher Adis International Ltd.
Collection year 2011
Language eng
Subject 111502 Clinical Pharmacology and Therapeutics
C1
920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified
Formatted abstract
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 (rs1128503) and ABCB1 2677G>TA (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 pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4-392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5ast;1 wild-type allele compared with homozygous carriers of a CYP3A5ast;3 variant allele. Carriers of a CYP3A5ast;1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>TA SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. 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 useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy.
© 2010 Adis Data Information BV. All rights reserved.
Keyword Renal-transplant recipients
Tacrolimus dose requirements
Steady-state pharmacokinetics
Donor liver-transplantation
Mdr1 genetic polymorphisms
Multidrug-resistance gene
Healthy Japanese subjects
P-glycoprotein activity
Cyclosporine pharmacokinetics
Clinical presentation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Pharmacy Publications
 
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Created: Sun, 04 Apr 2010, 00:06:33 EST