Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients.
OBJECTIVE
To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients.


METHODS
Pharmacogenetic analysis of patients enrolled in a previously published study.


METHODS
One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation.


RESULTS
ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05).


CONCLUSIONS
The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Fabiana D V
http://orcid.org/0000-0002-7112-2879
FDV
Genvigir
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Alvaro M
AM
Nishikawa
Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
Claudia R
CR
Felipe
Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
Helio
H
Tedesco-Silva
Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
Nagilla
N
Oliveira
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Antony B C
ABC
Salazar
Nephrology Division, Hospital do Rim, Federal University of Sao Paulo, Sao Paulo, Brazil.
Jose O
JO
Medina-Pestana
School of Medicine, Uniformed Services University, Bethesda, Maryland.
Sonia Q
SQ
Doi
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Mario H
MH
Hirata
Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Rosario D C
RDC
Hirata
D000328:Adult; D001938:Brazil / Q000453:epidemiology; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009173:Mycophenolic Acid / Q000097:blood / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome
D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D016559:Tacrolimus; C000715087:ABCC2 protein, human; C000717350:CYP2J2 protein, human; C450259:CYP2C8 protein, human

ABCC2
; 
ABCG2
; 
CYP2C8
; 
CYP2J2
; 
UGT2B7
; kidney transplantation; mycophenolate sodium; polymorphism; tacrolimus