The Influence of Norfloxacin and Metronidazole on the Disposition of Mycophenolate Mofetil

Abstract

The objective of this study was to investigate the effect of concurrent antibiotic administration on the disposition of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) after oral administration of mycophenolate mofetil (MMF) in healthy subjects. Eleven healthy subjects were enrolled. The study was divided into 4 treatment periods. Subjects received MMF as a single oral 1-g dose alone and were then randomized to 3 antibiotic treatment periods. The 3 periods included norfloxacin, metronidazole, and a combination of norfloxacin and metronidazole. Antibiotic treatment was started 3 days prior to each MMF pharmacokinetic study day and was given for a total of 5 days. On day 4 of each antibiotic phase, subjects received a single 1-g oral dose of MMF. Plasma and urine samples were obtained over 48 hours after the MMF dose in all treatment periods and were quantitatively measured for MPA and MPAG. Pharmacokinetic parameters for MPA and MPAG were determined for all periods. Compared to MMF alone, the area under the plasma concentration versus time curve (AUC) of MPA was reduced by an average of 10%, 19%, and 33% when given with norfloxacin, metronidazole, and norfloxacin plus metronidazole, respectively. The AUC of MPAG was also reduced on average by 10%, 27%, and 41% in the corresponding periods. The combination of norfloxacin and metronidazole significantly reduced the AUC of MPA and MPAG in healthy subjects. This likely occurs as a result of reduced enterohepatic recirculation.

New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

“…First, there is a clear association between MPA exposure and efficacy, defined as the prevention of acute rejection. [2][3][4][5][127][128][129][130][131][132] Second, the pharmacokinetics of MPA display a high interpatient variability, 130,133 and over the years, numerous factors contributing to this high variability, including renal [133][134][135][136][137][138][139][140] and hepatic impairment, 133 [163][164][165][166][167][168][169][170], and genetic polymorphisms, [171][172][173][174][175][176][177][178][179][180][181] have been identified (Table 1). On the other hand, the lack of a clear relationship between MPA exposure and drug-related toxicity raises doubts about the usefulness of MPA TDM in clinical practice.…”

“…224 The reduced MPA exposure in patients treated with antibiotics is likely to be due to reduced bacterial deglucuronidation of MPAG in the colon, which leads to a decreased enterohepatic recirculation of MPA/MPAG. [163][164][165] Interestingly, a recent study in renal allograft recipients illustrated that drug-drug interactions involving the phase II metabolism of MPA (ie, glucuronidation by UGT isoenzymes) can lead to marked changes in MPA pharmacokinetics as well. In this study, 1-week coadministration of rifampin led to a significant and important decrease in MPA exposure and a significant increase in both MPAG and AcMPAG exposure in all patients.…”

Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

“…Small bowel decontamination and antibiotics such as norfloxacin and metronidazole reduce MPA exposure by affecting its absorption, whereas cholestyramine inhibits the enterohepatic recirculation (21)(22)(23). Proton pump inhibitors (e.g., pantoprazole, lansoprazole) reduce hydrolysis of MMF and hence MPA concentrations (24,25).…”

Legemiddelinteraksjoner og immunsuppresjon hos organtransplanterte

“…Dette legemidlet bremser proliferasjonen av aktiverte lymfocytter ved å hemme syntesen av (deoksy)guaninnukleotider (29). Aktuelle legemiddelinteraksjoner for mykofenolat er oppsummert i tabell 2 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”