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Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients

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Abstract

Background and Objective

Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus.

Subjects and Methods

A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (−24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling.

Results

Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5-fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 × (age/50)−0.78 × 2.03 (CYP3A5 expressers) × 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus.

Conclusions

This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.

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Acknowledgments

This research is funded in part by R15 GM101599 from the National Institutes of Health. Some of the work was conducted at the Rhode Island Genomics and Sequencing Center, which is supported in part by the National Science Foundation (MRI grant DBI-0215393 and EPSCoR Awards 0554548 & 1004057), the US Department of Agriculture (grants 2002-34438-12688, 2003-34438-13111 & 2008-34438-19246), and the University of Rhode Island. The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, 7 Greenhouse Road, Kingston, RI, 02881, USA

    Ken Ogasawara, Shripad D. Chitnis & Fatemeh Akhlaghi

  2. Division of Organ Transplantation, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Reginald Y. Gohh

  3. iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Denver, Aurora, CO, USA

    Uwe Christians

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  1. Ken Ogasawara
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  2. Shripad D. Chitnis
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  3. Reginald Y. Gohh
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  4. Uwe Christians
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  5. Fatemeh Akhlaghi
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Correspondence to Fatemeh Akhlaghi.

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Ogasawara, K., Chitnis, S.D., Gohh, R.Y. et al. Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients. Clin Pharmacokinet 52, 751–762 (2013). https://doi.org/10.1007/s40262-013-0069-2

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