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Abstract: SA-PO282

Association Between Mycophenolic Acid (MPA) Pharmacokinetics and In Vitro MPA Glucuronide (MPAG) Turnover by Gut Microbiota of Kidney Transplant Recipients

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Onyeaghala, Guillaume Chinedu, Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
  • Vo, Duy, Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
  • Mohamed, Moataz, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Saqr, Abdelrahman, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Brito Sanchez, Bryan P., Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
  • Elmer, Sarah, Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
  • Hunter, Ryan C., University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Teigen, Levi, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Dorr, Casey R., Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
  • Staley, Christopher, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Wu, Baolin, University of California Irvine, Irvine, California, United States
  • Guan, Weihua, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • El-Rifai, Rasha, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Matas, Arthur J., University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Oetting, William S., University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Jacobson, Pamala A., University of Minnesota Twin Cities, Minneapolis, Minnesota, United States
  • Israni, Ajay K., Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States
Background

Pharmacokinetic (PK) studies show enterohepatic recycling (EHR) of mycophenolic acid (MPA) due to MPA glucuronide (MPAG) hydrolysis by gut b-glucuronidases (BGUS). EHR increases MPA systemic exposure and likely enhances immunosuppression and toxicity in kidney transplant recipients (KTRs). We hypothesized that extensive EHR in-vivo would correlate with higher MPAG to MPA in-vitro.

Methods

9 KTRs underwent simultaneous PK and stool collection at 30-60 days post-transplant. MPA % EHR was defined as MPA AUC5-12 hour / AUC0-12 hour x 100. Stool samples were anaerobically exposed to 100 mg/mL of MPAG in 7mL of YCFA (Yeast extract-Casein hydrolysate-fatty acids) broth, with aliquots collected at 0, 30, 60, 90 and 120 minutes. Total MPA and MPAG concentrations were assessed using mass spectrometry. Microbiota were characterized by 16S sequencing. We applied the Louvain Modularity Maximization algorithm to the correlation between in-vitro MPA levels, MPA PK, and BGUS producers present in >10% of samples (Threshold R=0.3).

Results

After exposure to MPAG, we observed an increase in MPA with a concurrent decrease in MPAG concentrations across all in-vitro samples. Further comparison showed a positive correlation between MPA AUC and in-vitro MPA at 0, 30, 60, 90 and 120 mins post incubation (R = 0.85, 0.68, 0.58, 0.48, 0.43 respectively, p < 0.05 at 0 and 30 mins). We included 7 out of 31 previously known BGUS producers in our network analyses, which suggested that the relative abundances of B. uniformis, R. gnavus and C. aerofaciens correlated with in-vitro MPA in the first hour and MPA AUC (FIG 1).

Conclusion

These data suggest that MPAG metabolism to MPA by the stool microbiome is correlated to the relative abundance of known BGUS producers. Further studies are needed to associate the extent of MPA PK with BGUS producers.

Funding

  • NIDDK Support