Clinical relevance and prevalence of polymorphisms in CYP3A5 and MDR1 genes that encode tacrolimus biotransformation enzymes in liver transplant recipients.
OBJECTIVE
To study the prevalence and clinical significance of polymorphisms in the CYP3A5 and MDR1 genes in liver transplant patients and their donors; to determine the relative importance of genes from the donor and the recipient; to assess the relationship of polymorphisms with the variability of concentration/dose of tacrolimus for optimization and individualization regimens.


METHODS
This prospective study included 53 liver transplant recipients who received tacrolimus de novo. CYP3A5 and MDR1 gene polymorphisms were identified in the donors and recipients using polymerase chain reaction. We collected indicator variables of graft function and the patient for 3 months after the transplantation: days 0, 1, 3, 7, 14, 30, 60, and 90.


RESULTS
The frequencies of CYP3A5 polymorphisms were: 90.6% (G/G), 9.4% (G/A) and 0% (A/C) in donors and 88.7% (G/G), 11.3% (G/A), and 0% (A/A) in recipients. For the MDR1 gene, they were: 26.4% (C/C), 50.9% (C/T), and 22.6% (T/T) in donors and 17.0% (C/C), 71.7% (C/T), and 11.3% (T/T) in recipients. In the early days after transplant, G/A recipients from G/A donors did not reach the minimum drug levels. Between days 30 and 60, G/G recipients from G/A donors required higher tacrolimus doses. G/G recipients (CYP3A5) from C/T donors (MDR1) had a lower frequency of renal dysfunction, the same rejection rate, and a higher rate of diabetes than the other groups.


CONCLUSIONS
For CYP3A5, the presence of the A allele appeared to be related to greater requirements for tacrolimus in the early days after transplantation. Pharmacogenetics combined with pharmacodynamics may be a useful tool to adjust the concentration of tacrolimus depending on the absorption by the individual patient.
Barrera-Pulido
L
L
Hepatobiliopancreatic Unit of Surgery and Liver Transplantation, Virgen del Rocío Hospitals, Sevilla, Spain. lydiabarrera@hotmail.com
Aguilera-García
I
I
Docobo-Pérez
F
F
Alamo-Martínez
J M
JM
Pareja-Ciuró
F
F
Nuñez-Roldán
A
A
Gómez-Bravo
M A
MA
Bernardos-Rodríguez
A
A
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003920:Diabetes Mellitus / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005787:Gene Frequency; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016031:Liver Transplantation / Q000502:physiology*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000453:epidemiology; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014019:Tissue Donors / Q000706:statistics & numerical data; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus