Abstract
Introduction. Polymorphism ABCG2 c.421C>A(rs2231142) results in a reduced activity of the important drug efflux
transporter breast cancer resistance protein (BCRP/ABCG2). One study
suggested that it may affect enterohepatic recirculation of mycophenolic
acid (MPA). We evaluated the effect rs2231142 on steady-state exposure
to MPA in renal transplant recipients.
Methods . Consecutive, stable adult (age ≥16 years) renal
transplant recipients on standard MPA-based immunosuppressant protocols
(N=68, 43 co-treated with cyclosporine, 25 with tacrolimus) underwent
routine therapeutic drug monitoring after a week of initial treatment,
and were genotyped for ABCG2 c.421C>A and 11
polymorphisms in genes encoding enzymes and transporters implicated in
MPA pharmacokinetics. ABCG2 c.421C>A variant vs.
wild-type (wt) patients were matched in respect to demographic,
biopharmaceutic and genetic variables (full optimal combined with exact
matching) and compared for dose-adjusted steady-state MPA
pharmacokinetics (frequentist and Bayes [skeptical neutral prior]
estimates of geometric means ratios, GMR).
Results . Raw data (12 variant vs. 56 wt patients) indicated by
around 40% higher total exposure (frequentist GMR=1.45, 95%CI
1.10-1.91; Bayes = 1.38, 95%CrI 1.07-1.81) and by around 30% lower
total body clearance (frequentist GMR=0.66, 0.58-0.90; Bayes=0.71,
0.53-0.95) in variant carriers than in wt controls. The estimates were
similar in matched data (11 variant vs. 43 wt patients): exposure
GMR=1.41 (1.11-1.79) frequentist, 1.39 (1.15-1.81) Bayes, with 90.7%
and 85.5% probability of GMR >1.20, respectively;
clearance GMR=0.73 (0.58-0.93) frequentist, 0.71 (0.54-0.95) Bayes.
Sensitivity analysis indicated high unsusceptibility of the estimates to
unmeasured confounding.
Conclusions . Loss-off-function polymorphism ABCG2
c.421C>A increases steady-state exposure to MPA in stable
renal transplant patients.
Key words : mycophenolic acid, renal transplant, breast cancer
resistance protein, polymorphism