CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing.
OBJECTIVE
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.
Hospital Infantil de México Federico Gómez, Mexico City, Mexico.
Pilar
P
García-Roca
Mara
M
Medeiros
Herlinda
H
Reyes
Benjamín Antonio
BA
Rodríguez-Espino
Josefina
J
Alberú
Lourdes
L
Ortiz
Mayela
M
Vásquez-Perdomo
Guillermo
G
Elizondo
Luis Eduardo
LE
Morales-Buenrostro
Eduardo
E
Mancilla Urrea
Gilberto
G
Castañeda-Hernández
D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001682:Biological Availability; D001711:Biotransformation / Q000235:genetics; D044383:Black People / Q000235:genetics; D002648:Child; D018389:Codon, Nonsense; D003430:Cross-Sectional Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000502:physiology; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008800:Mexico; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
D018389:Codon, Nonsense; D007166:Immunosuppressive Agents; D020033:Protein Isoforms; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus