Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject
variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which
show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX.
Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate
the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics.
Methods: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients.
For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic
analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties
analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional
estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition
Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283,
and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes
were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1)
=8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h-
Conclusion: In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor
should be considered when determining MTX dosing. However, prospective studies with a large number of participants
are needed to validate the results of this study.