Original ArticleClinicalCYP3A5 Polymorphism in Mexican Renal Transplant Recipients and its Association with Tacrolimus Dosing
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.
References (33)
- et al.
The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation
Am J Transplant
(2004) Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection
Drugs
(2009)- et al.
Pharmacodynamic approach to immunosuppressive therapies using calcineurin inhibitors and mycophenolate mofetil
Clin Chem
(2003) - et al.
Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus
Fundam Clin Pharmacol
(2009) - et al.
Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome
Transplantation
(2008) - et al.
Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient’s CYP3A5 genotype in tailoring treatment
Biopharm Drug Dispos
(2010) - et al.
Genetic variations in ABCB1 and CYP3A5 as well as sex influence quinine disposition among Ugandans
Ther Drug Monit
(2010) - et al.
Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety
J Clin Pharmacol
(2010) - et al.
Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients
J Clin Pharm Ther
(2009) - et al.
CYP3A5 but not CYP2D6 polymorphism contributes significantly to the variability in dextropropoxyphene disposition
J Clin Pharmacol
(2010)
Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement
Transplantation
A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype
Transplantation
Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation
Clin Pharmacokinet
Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients
Transplantation
Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico
Proc Natl Acad Sci USA
Pharmacokinetics of oral nifedipine in different populations
J Clin Pharmacol
Cited by (36)
Pharmacogenomics of immunosuppressants
2023, Pharmacogenomics: from Discovery to Clinical ImplementationCYP3a5 Genetic Polymorphism in Chinese Population With Renal Transplantation: A Meta-Analysis Review
2022, Transplantation ProceedingsOral Ciprofloxacin Pharmacokinetics in Healthy Mexican Volunteers and Other Populations: Is There Interethnic Variability?
2020, Archives of Medical ResearchCitation Excerpt :It is clear that data on interethnic variability cannot be readily generalized (2). In the case of the Mexican population, it has been reported that the pharmacokinetics of certain drugs, such as nifedipine (40,47) and tacrolimus (48) differ with regard to Caucasians, but are similar to that of South Asians. It has been reported that meloxicam pharmacokinetics in Mexicans differ from Caucasians but are similar to Chinese (38).
The Many Faces of Calcineurin Inhibitor Toxicity—What the FK?
2020, Advances in Chronic Kidney DiseaseCitation Excerpt :The therapeutic effects of FK are prolonged relative to CsA owing to a highly active metabolite with equal immunosuppressive potency to the parent drug, compared to CsA metabolites that have only 10%-20% of parent drug activity. Polymorphisms resulting in CYP3A5 loss of function may also significantly influence drug metabolism and exposure, and lead to higher incidence of CNI-related nephrotoxicity.15-19 Similarly, polymorphisms in ABCB1 which encodes the efflux transporter P-glycoprotein present in enterocytes, hepatocytes, and kidney cells may influence oral bioavailability and drug clearance as well as CNI concentrations in kidney tubular epithelial cells.20
Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients
2019, Biology of Blood and Marrow TransplantationCitation Excerpt :There has been great interest in identifying the genetic underpinnings of the considerable variability in tacrolimus exposure to provide a personalized rather than empiric dosing approach, with the goal to optimize drug exposure and clinical response. Findings from previous pharmacogenetic studies revealed that single nucleotide polymorphisms (SNPs) in the pharmacokinetic gene, CYP3A5 (primarily the *3 allele, which is the most prevalent variant allele across most racial groups, especially whites), was the single most important determinant of the observed tacrolimus variability after oral administration [9–12]. Because the CYP3A5*3 variant allele is associated with reduced expression of the enzyme responsible for metabolizing tacrolimus, patients homozygous for this polymorphism (ie, harbor 2 copies of CYP3A5*3, referred to as CYP3A5 nonexpressers) require lower oral doses of the drug to achieve therapeutic concentrations compared with those carrying 1 copy of CYP3A5*3 or homozygous for the wild-type allele (CYP3A5*1/*1) [13].
CYP3A5 Genotype and Time to Reach Tacrolimus Therapeutic Levels in Renal Transplant Children
2016, Transplantation ProceedingsCitation Excerpt :An ethnic variation in CYP3A5 allelic frequency has been reported by several authors, with 5%–15% of whites expressing the enzyme in contrast to 70%–80% of African Americans and 30% of Asians [6–8]. In Mexican renal transplant recipients, the frequency is 50% [2]. The expression of the enzyme has been related to tacrolimus dose requirements but not to acute rejection, probably because patients end up having the target concentrations owing to therapeutic drug monitoring [9].