Change in pharmacokinetics of mycophenolic acid as a function of age in rats and effect of coadministered amoxicillin/clavulanate.
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.
Department of Clinical Drug Informatics, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan. junishi@p.kanazawa-u.ac.jp
Junko
J
Ishizaki
Tomoko
T
Tsuda
Yukio
Y
Suga
Satsuki
S
Ito
Kunizo
K
Arai
Yoshimichi
Y
Sai
Ken-Ichi
K
Miyamoto
D000367:Age Factors; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001646:Bile / Q000737:chemistry; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D019980:Amoxicillin-Potassium Clavulanate Combination; D009173:Mycophenolic Acid