CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing

Arch Med Res. 2012 May;43(4):283-7. doi: 10.1016/j.arcmed.2012.05.005. Epub 2012 Jun 13.

Abstract

Background and aims: Variability in CYP3A5 expression associated with differences in tacrolimus bioavailability has been documented. The wild-type allele CYP3A5*1 expresses the functional protein, whereas the CYP3A5*3 allele is a splice variant with a premature stop codon and encodes a truncated nonfunctional protein. The aim of the study was to determine the frequency of CYP3A5*1 and CYP3A5*3 in 291 (124 adults, 167 pediatric) Mexican renal transplant recipients, evaluate the tacrolimus dose requirements by genotype and compare genotype frequency data with that of other populations.

Methods: We carried out a multicenter study. Patients were recruited from three institutions located in Mexico City. Genotyping of the CYP3A5*1 and CYP3A5*3 alleles was performed by direct DNA sequencing.

Results: Eighteen patients (6.2%) were CYP3A5*1*1 homozygous carriers or functional protein expresser homozygous, 121 patients (41.6 %) were CYP3A5*1*3 were heterozygous carriers or heterozygous expressers, and 152 patients (52.2%) were CYP3A5*3*3 homozygous carriers or homozygous nonexpressers. There was a statistically significant difference in frequency of the functional and nonfunctional expresser phenotypes from those reported for Black and Caucasian, but not for South Asian populations. The CYP3A5 phenotype had a significant impact in tacrolimus bioavailability, as wild-type carriers required higher dosing compared to mutated carriers to achieve similar drug trough levels. Patients with CYP3A5*1*1 genotype had a median dose requirement of 0.16 mg/kg/day, CYP3A5*1*3 patients had a median tacrolimus dose of 0.13 mg/kg/day and CYP3A5*3*3 had a median dose of 0.07 mg/kg/day (Kruskal-Wallis, p <0.0001).

Conclusions: Of the Mexican transplant recipients, 52.2% were CYP3A5*3*3 and required significantly lower tacrolimus dose than those with CYP3A5*1 allele.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • African Continental Ancestry Group / genetics
  • Alleles
  • Asian Continental Ancestry Group / genetics
  • Biological Availability
  • Biotransformation / genetics
  • Child
  • Codon, Nonsense
  • Cross-Sectional Studies
  • Cytochrome P-450 CYP3A / genetics*
  • Cytochrome P-450 CYP3A / physiology
  • Ethnic Groups / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics*
  • Kidney Transplantation*
  • Male
  • Mexico
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protein Isoforms / genetics
  • Tacrolimus / administration & dosage
  • Tacrolimus / pharmacokinetics*
  • Young Adult

Substances

  • Codon, Nonsense
  • Immunosuppressive Agents
  • Protein Isoforms
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • Tacrolimus