Original Article
Clinical
CYP3A5 Polymorphism in Mexican Renal Transplant Recipients and its Association with Tacrolimus Dosing

https://doi.org/10.1016/j.arcmed.2012.05.005Get rights and content

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.

Introduction

Tacrolimus is a calcineurin inhibitor widely used to prevent rejection in organ transplantation (1). It exhibits a narrow therapeutic index as well as highly variable pharmacokinetics and a steep concentration-effect relationship in a manner that adequate dosing requires individualization and continuous adjustments on the basis of therapeutic drug monitoring 2, 3. It is well documented that tacrolimus metabolism depends upon liver and intestine expression of the phase I metabolizing enzymes CYP3A4 and CYP3A5. Moreover, it is known that there is a wide variation in the expression and function of these enzymes, sometimes related to genetic polymorphisms (4). A single nucleotide polymorphism in the intron 3 of CYP3A5 gene is determinant for the expression of the protein. The wild-type allele, CYP3A5*1 (A6986), produces the functional protein, whereas the mutated CYP3A5*3 allele (6986G) has a premature stop codon and produces a truncated nonactive protein. The expresser phenotype results from homozygous CYP3A5*1*1 and the heterozygous CYP3A5*1*3 genotype. The nonexpresser phenotype is given by the homozygous CYP3A5*3*3 genotype. There is evidence that individuals with the wild-type phenotype may require higher doses of several drugs such as sirolimus (5), quinine (6), risperidone (7), carbamazepine (8), dextropropoxyphene (9) and tacrolimus 2, 10, 11, 12, 13, 14 in order to achieve a similar bioavailability compared to mutated carriers.

The frequency of the CYP3A5 alleles exhibits interethnic variability. It has been reported that expresser phenotype is more frequent in African-Americans compared to South Asians and Caucasians 11, 12. Information on CYP3A4 genotypes and their influence of drug dosing in the Mexican population, however, is wanting. It is known that 90% of the Mexican population consists of Mestizos exhibiting a mixture of Amerindian, European, and African ancestries (15). Furthermore, there is evidence that the pharmacokinetics of drugs whose biotransformation depends on CYP3A4/CYP3A5 activity including nifedipine 16, 17, midazolam (18), cyclosporine (19), sildenafil (20), omeprazole (21) and meloxicam (22) are different in Mexicans with regard to Caucasian subjects. Therefore, dosing regimens derived for Caucasians cannot be blindly extrapolated to the Mexican population. It is necessary to perform clinical, pharmacokinetic and pharmacogenetic studies in Mexicans, particularly for drugs with narrow therapeutic indices for which dosing errors may produce severe consequences, as is the case of tacrolimus. Hence, the present study was undertaken to determine the frequency of the CYP3A5*1 and CYP3A5*3 alleles in Mexican renal transplant recipients and to examine the impact of genotype on tacrolimus dosing. Additionally, comparisons were made between the results observed in Mexicans with those reported for other ethnic groups.

Section snippets

Study Design

A cross-sectional clinical study was performed in patients from three renal transplant centers in Mexico City: Hospital Infantil de México Federico Gómez, Instituto Nacional de Cardiología Ignacio Chávez and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. The study was conducted according to the principles of the revised World Medical Association’s Declaration of Helsinki and was approved by the Institutional Internal Review Boards and Ethics Committees. Written informed

Results

The study included 291 Mexican renal transplant recipients recruited from three centers in Mexico City. Patient demographic data are provided in Table 1; there were 124 adults and 167 pediatric recipients. The age of the transplant recipients for pediatric and adult patients was similar to other reported Mexican series 24, 25.

Genotype distribution and allele frequencies are depicted in Table 2. The CYP3A5*1*1 genotype, yielding homozygous expressers of the functional enzyme, was rare. It was

Discussion

It is documented that 90% of the Mexican population consists of Mestizos exhibiting a mixture of Amerindian, European, and African ancestries (15). Hence, differences in drug metabolizing genotypes and phenotypes between Mexicans and other populations can be expected. It has been observed that the pharmacokinetics of certain drugs such as nifedipine 16, 17, midazolam (18), cyclosporine (19), sildenafil (20), omeprazole (21) and meloxicam (22) are different in Mexican as opposed to Caucasian

Conflict of Interest

All authors declare no competing interests.

Acknowledgments

This work was supported by CONACYT, grant 2008-COI-87327 and by Mexican Federal Funds from the Hospital Infantil de México Federico Gómez HIM/2008/020 SSa (806). M. Vásquez-Perdomo was supported by PROBEI.

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