Effects of uridine diphosphate glucuronosyltransferase 2B7 and 1A7 pharmacogenomics and patient clinical parameters on steady-state mycophenolic acid pharmacokinetics in glomerulonephritis.
OBJECTIVE
The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA).


METHODS
A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling.


RESULTS
In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R (2)=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R (2)=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient -0.4647; R (2) 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p < 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p < 0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine.


CONCLUSIONS
Clinical and demographic parameters were 2-4 times more important in MPA disposition than genotypes and explained 30-40% of the pharmacokinetic parameters.
Joy
Melanie S
MS
School of Medicine, UNC Kidney Center, University of North Carolina, Chapel Hill, NC, USA. Melanie_Joy@med.unc.edu
Boyette
Tammy
T
Hu
Yichun
Y
Wang
Jinzhao
J
La
Mary
M
Hogan
Susan L
SL
Stewart
Paul W
PW
Falk
Ronald J
RJ
Dooley
Mary Anne
MA
Smith
Philip C
PC
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9; D014657:Vasculitis / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000276:immunology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019268:Antibodies, Antineutrophil Cytoplasmic; D015415:Biomarkers; D004791:Enzyme Inhibitors; C000715591:UGT1A9 protein, human; D003404:Creatinine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C524630:UGT1A7 protein, human; D009173:Mycophenolic Acid