Pharmacogenetic impact of UDP-glucuronosyltransferase metabolic pathway and multidrug resistance-associated protein 2 transport pathway on mycophenolic acid in thoracic transplant recipients: an exploratory study.
OBJECTIVE
To assess the contribution of polymorphisms in the uridine diphosphate glucuronosyltransferase gene (UGT) and the multidrug resistance-associated protein 2 gene (ABCC2) to mycophenolic acid (MPA) pharmacokinetics and clinical outcomes in thoracic transplant recipients.


METHODS
Open-label, cross-sectional study.


METHODS
Transplant clinic in Vancouver, British Columbia, Canada.


METHODS
Sixty-eight thoracic (36 lung, 32 heart) transplant recipients who were receiving steady-state oral mycophenolate mofetil.


RESULTS
Eleven blood samples were obtained from each patient over a 12-hour dosing period. Plasma concentrations of MPA (active metabolite of mycophenolate mofetil), the MPA metabolites 7-Omycophenolic acid glucuronide (MPAG) and acyl glucuronide (AcMPAG), and free MPA were measured, and dose-normalized conventional pharmacokinetic parameters were determined by noncompartmental methods. Genetic polymorphisms in UGT and ABCC2 were determined by sequencing, and their contributions to pharmacokinetic variability were investigated by using multivariate analysis. For both the lung and heart transplant groups, the UGT2B7 variant 802T (Tyr(268) or UGT2B7*2, rs7439366) and the UGT2B7 variant -138A modified AcMPAG exposure (2.5-3.7-fold and 9.3-12.3-fold higher AcMPAG area under the concentration-time curve [AUC] and AcMPAG:MPA ratio, respectively). In an exploratory analysis, occurrences of rejection, infection, anemia, and leukopenia were associated with an AcMPAG AUC greater than 50 μg·hour/ml and an AcMPAG:MPA ratio greater than 2.


CONCLUSIONS
UGT2B7 is a promising gene candidate that may influence MPA pharmacokinetics clinically; however, larger clinical pharmacogenetic studies in thoracic transplant subpopulations are warranted to corroborate the role of AcMPAG and UGT2B7 variants in optimizing mycophenolate mofetil therapy.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Lillian S L
LS
Ting
Marie-Odile
MO
Benoit-Biancamano
Olivier
O
Bernard
K Wayne
KW
Riggs
Chantal
C
Guillemette
Mary H H
MH
Ensom
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001955:British Columbia; D003430:Cross-Sectional Studies; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D016027:Heart Transplantation / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016040:Lung Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; C000715087:ABCC2 protein, human