Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation

Harini M Chakkera, Y. H. Chang, J. K. Bodner, S. Behmen, R. L. Heilman, Kunam Sudhakar Reddy, D. C. Mulligan, A. A. Moss, H. Khamash, N. Katariya, W. R. Hewitt, T. L. Pitta, L. A. Frassetto

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Abstract

Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P =.002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P =.4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the*3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.

Original languageEnglish (US)
Pages (from-to)137-141
Number of pages5
JournalTransplantation Proceedings
Volume45
Issue number1
DOIs
StatePublished - Jan 2013

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North American Indians
Tacrolimus
Kidney Transplantation
Single Nucleotide Polymorphism
Cytochrome P-450 CYP3A
Pharmacokinetics
Kidney
Membrane Transport Proteins
Enzymes
Pharmaceutical Preparations
Genotype

ASJC Scopus subject areas

  • Surgery
  • Transplantation

Cite this

Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation. / Chakkera, Harini M; Chang, Y. H.; Bodner, J. K.; Behmen, S.; Heilman, R. L.; Reddy, Kunam Sudhakar; Mulligan, D. C.; Moss, A. A.; Khamash, H.; Katariya, N.; Hewitt, W. R.; Pitta, T. L.; Frassetto, L. A.

In: Transplantation Proceedings, Vol. 45, No. 1, 01.2013, p. 137-141.

Research output: Contribution to journalArticle

Chakkera, HM, Chang, YH, Bodner, JK, Behmen, S, Heilman, RL, Reddy, KS, Mulligan, DC, Moss, AA, Khamash, H, Katariya, N, Hewitt, WR, Pitta, TL & Frassetto, LA 2013, 'Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation', Transplantation Proceedings, vol. 45, no. 1, pp. 137-141. https://doi.org/10.1016/j.transproceed.2012.10.023
Chakkera, Harini M ; Chang, Y. H. ; Bodner, J. K. ; Behmen, S. ; Heilman, R. L. ; Reddy, Kunam Sudhakar ; Mulligan, D. C. ; Moss, A. A. ; Khamash, H. ; Katariya, N. ; Hewitt, W. R. ; Pitta, T. L. ; Frassetto, L. A. / Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation. In: Transplantation Proceedings. 2013 ; Vol. 45, No. 1. pp. 137-141.
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