Change in Pharmacokinetics of Mycophenolic Acid as a Function of Age in Rats and Effect of Coadministered Amoxicillin/Clavulanate

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  • Ishizaki Junko
    Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
  • Tsuda Tomoko
    Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
  • Suga Yukio
    Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
  • Ito Satsuki
    Department of Hospital Pharmacy, Kanazawa University School of Medicine
  • Arai Kunizo
    Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
  • Sai Yoshimichi
    Department of Hospital Pharmacy, Kanazawa University School of Medicine Department of Medicinal Informatics, Graduate School of Medical Science, Kanazawa University
  • Miyamoto Ken-ichi
    Department of Hospital Pharmacy, Kanazawa University School of Medicine Department of Medicinal Informatics, Graduate School of Medical Science, Kanazawa University

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Abstract

Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug–drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles.

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