Abstract
Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and is under investigation for its efficacy against osteosarcoma. We investigated the genetic variability of whole-exome sequencing (WES) data from osteosarcoma patients and healthy volunteers who receive mycophenolate mofetil (MMF), a prodrug of MPA. Using the whole-exome sequencing (WES), we found 95 single nucleotide polymorphisms (SNPs) in osteosarcoma patients and 118 SNPs in healthy volunteers based on the list of genes related to MPA and its metabolite (MPAG) metabolism. For osteosarcoma patients, variants located in the gene UGT1A8, SLCO1B3, IMPDH1, ABCC3, UGT1A6, and UGT1A7 were related to some pharmacokinetic parameters of MPA and MPAG. For healthy volunteers, variants located in the gene SLCO1B3, SLCO1B1, and CYP2C8 were found to be in relation to some pharmacokinetic parameters of MPA and MPAG. In addition, we examined the effects of trimethoprim-sulfamethoxazole (TMP-SMX) on gut microbiota and the pharmacokinetics of MPA and MPAG when co-administered with MMF in healthy volunteers. The results have shown that TMP-SMX could alter the structure of the gut bacterial community. TMP-SMX treatment significantly decreased the relative abundance of genus Bacteroides, a major group of β-glucuronidase-producing bacteria in the gut. Moreover, concomitant administration of TMP-SMX with MMF also significantly reduced the area under the concentration-time curve from time 0 extrapolated to infinite time (AUC0-∞) of MPA. These results imply that TMP-SMX may interfere with the enterohepatic recirculation of MPA by decreasing gut bacterial β-glucuronidase enzymes that are responsible for regenerating MPA from its glucuronide metabolite MPAG, resulting in the reduction of MPA exposure.
