Document Detail


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.
MedLine Citation:
PMID:  20973683     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
DESIGN: Open-label, cross-sectional study.
SETTING: Transplant clinic in Vancouver, British Columbia, Canada.
PATIENTS: Sixty-eight thoracic (36 lung, 32 heart) transplant recipients who were receiving steady-state oral mycophenolate mofetil.
MEASUREMENTS AND MAIN 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.
CONCLUSION: 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.
Authors:
Lillian S L Ting; Marie-Odile Benoit-Biancamano; Olivier Bernard; K Wayne Riggs; Chantal Guillemette; Mary H H Ensom
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmacotherapy     Volume:  30     ISSN:  1875-9114     ISO Abbreviation:  Pharmacotherapy     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-26     Completed Date:  2011-03-03     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8111305     Medline TA:  Pharmacotherapy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1097-108     Citation Subset:  IM    
Affiliation:
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Area Under Curve
British Columbia
Cross-Sectional Studies
Female
Glucuronosyltransferase / genetics*
Heart Transplantation / methods
Humans
Immunosuppressive Agents / pharmacokinetics,  therapeutic use
Lung Transplantation / methods
Male
Middle Aged
Multidrug Resistance-Associated Proteins / genetics*
Multivariate Analysis
Mycophenolic Acid / analogs & derivatives*,  pharmacokinetics,  therapeutic use
Pharmacogenetics
Polymorphism, Genetic
Retrospective Studies
Treatment Outcome
Young Adult
Grant Support
ID/Acronym/Agency:
MOP-133946//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Immunosuppressive Agents; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 2; 24280-93-1/Mycophenolic Acid; 9242ECW6R0/mycophenolate mofetil; EC 2.4.1.17/Glucuronosyltransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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