Influence of calcineurin inhibitors and genetic polymorphism of
transporters on enterohepatic circulation and exposure of mycophenolic
acid in Chinese adult renal allograft recipients
Abstract
Aim: Study the influence of calcineurin inhibitors (CNI) and genetic
polymorphisms of transporters on enterohepatic circulation (EHC) of
mycophenolic acid (MPA) in Chinese adult renal allograft recipients and
estimate the effect of various covariates on prediction performance of
MPA AUC0-12h. Method: MPA concentrations of 125 Chinese patients were
collected 0-12 hours after administration. Genotypes of transporters
were determined in 64 patients. The influence of type of CNI and genetic
polymorphisms on MPA exposure was studied. Shapley additive explanations
method was used to study the impact of sampling times and covariates
related to EHC on AUC0-12h. Extreme gradient boosting (XGboost) machine
learning-based model was established to predict AUC0-12h. Results:
Dn-AUC6-12h was significantly lower in patients co-administered with CsA
(P<0.05). When co-administered with TAC, for SLCO1B1 T521C or
ABCC C-24T, patients with wild-type genotype had significantly higher
dn-AUC6-12h (P <0.05). Patients with SLCO1B3 334T/699G alleles
had significantly lower dn-AUC6-12h than homozygotes (P=0.004). No
significant difference was found in CsA subgroup. For estimating
AUC0-12h, C0h, C2h, C8h, type of CNI, transporters genotypes and the
difference between C0h and C2h were retained in the final model, which
had good prediction performance (r2=0.9739). Conclusion: Patients
co-administered with CsA had lower MPA EHC than those who received TAC.
MPA EHC is affected by ABCC2 C-24T, SLCO1B3 T334G/G699A, and SLCO1B1
T521C genotypes in patients treated with TAC. Type of CNI and genetic
polymorphisms of transporters can improve prediction performance of MPA
AUC0-12h estimating model, developed using XGboost machine learning
method.