Pharmacokinetic Drug Interaction of Mycophenolate With Co-Amoxiclav in Renal Transplant Patients

Prabha, Ratna; Mathew, Binu; Annapandian, VM; Saravanakumar, K; Basu, Gopal; Tamilarasi, V; Fleming, DH

doi:10.1097/tp.0b013e31820a6a79

Cited by 14 publications

(17 citation statements)

References 5 publications

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“…Oral ciprofloxacin or amoxicillin with clavulanic acid reduced the 12 hour pre‐dose MPA concentration to 46% of pre‐antibiotic levels within 3 days of antibiotic commencement; MPA concentrations recovered after 14 days of antibiotics. A case series of two patients suggests amoxicillin and clavulanic acid decreased MPA AUC . The impact of antibiotics on MPA pharmacokinetics may differ based on the bacterial spectrum.…”

Section: Discussionmentioning

confidence: 99%

“…A case series of two patients suggests amoxicillin and clavulanic acid decreased MPA AUC. 32 The impact of antibiotics on MPA pharmacokinetics may differ based on the bacterial spectrum. A healthy volunteer (N ¼ 11) cross-over study reported that MPA AUC was reduced by an average of 10%, 19%, or 33% when MMF was given with norfloxacin, metronidazole, or norfloxacin plus metronidazole, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

Mager

Sandmaier

et al. 2013

The Journal of Clinical Pharma

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We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

Mager

Sandmaier

et al. 2013

The Journal of Clinical Pharma

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“…Recently, coadministration of co‐amoxiclav in patients taking MMF after renal transplantation decreased the AUC of MPA in two patients, and the AUC of MPA returned to normal in one patient several days after discontinuation of co‐amoxiclav . The MPAG–antibiotic interaction varied with different drugs and in different patients; thus, factors other than inhibition of β‐glucuronidase are also involved in the decrease of MPA production.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of ciprofloxacin on β‐glucuronidase‐mediated deconjugation of mycophenolic acid glucuronide

Kodawara

Masuda

Yano

et al. 2014

Biopharm & Drug Disp

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The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase.

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“…Multiple human clinical reports have indirectly implicated GUS involvement in MMF metabolism (40)(41)(42). increased tight junction permeability (45,46).…”

Section: Assessment Of Bacterial Gus Activity In Vivomentioning

confidence: 99%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has proven advantages over other immunosuppressive drugs but gastrointestinal (GI) side effects frequently limit its use. The pathways involved in the metabolism of the prodrug MMF and the bioactive derivative mycophenolic acid (MPA) are well characterized but the mechanism responsible for toxicity is unknown. Here we extend our previous observation that an intact gut microbiome is required for MMF-induced toxicity and demonstrate that gut bacterial metabolism is responsible for the GI inflammation and weight loss associated with MMF exposure. In mice consuming MMF, the introduction of vancomycin alone was sufficient to prevent or reverse MMF-induced weight loss and colonic inflammation. MMF induced the expansion of bacteria expressing b-glucuronidase (GUS) in the cecum and proximal colon. GUS activity, which is responsible for the catabolism of glucuronidated MPA (MPAG) to free MPA, was increased in the presence of MMF and eliminated by vancomycin. Vancomycin eliminated multiple Bacteroides spp. that flourished in the presence of MMF and prevented the breakdown of MPAG without negatively affecting serum MPA levels. Human data suggests that increased stool GUS activity can be associated with MMF-related toxicity. Our work provides a mechanism for the GI toxicity associated with MMF and a future direction for the development of therapeutics.3

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Pharmacokinetic Drug Interaction of Mycophenolate With Co-Amoxiclav in Renal Transplant Patients

Cited by 14 publications

References 5 publications

Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

Inhibitory effect of ciprofloxacin on β‐glucuronidase‐mediated deconjugation of mycophenolic acid glucuronide

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

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