Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes

Vietri, Maria Teresa; Pietrabissa, Andrea; Mosca, Franco; Gm, Pacifici

doi:10.1007/s00228-001-0407-4

Cited by 19 publications

(17 citation statements)

References 6 publications

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“…The average K m determined for three HLM samples (0.082 mM) closely agrees with the average K m determined for three different preparations of 1A9 enzyme (0.077 mM). Estimates of apparent K m of HLM samples for MPA in other studies have generally ranged between 0.2 and 0.6 mM (Vietri et al, 2000(Vietri et al, , 2002Bowalgaha and Miners, 2001;Shipkova et al, 2001). However, Bernard and Guillemette (2004) reported lower K m values, closer to the estimates in our study (0.15-0.27 mM, with two sets of pooled human liver micro- FIG.…”

Section: Discussionsupporting

confidence: 81%

An Investigation of Human and Rat Liver Microsomal Mycophenolic Acid Glucuronidation: Evidence for a Principal Role of Ugt1a Enzymes and Species Differences in Ugt1a Specificity

Miles¹,

Stern²,

Smith³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n ‫؍‬ 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K m ‫؍‬ 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liverexpressed UGT1A enzyme with significant activity and exhibited both high affinity (K m ‫؍‬ 0.077 mM) and high activity (V max ‫؍‬ 28 nmol ⅐ min ؊1 ⅐ mg for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.

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Section: Discussionsupporting

confidence: 81%

An Investigation of Human and Rat Liver Microsomal Mycophenolic Acid Glucuronidation: Evidence for a Principal Role of Ugt1a Enzymes and Species Differences in Ugt1a Specificity

Miles¹,

Stern²,

Smith³

et al. 2005

Drug Metab Dispos

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“…The NSAIDs tested in this study also showed inhibitory potency against the glucuronidation of mycophenolic acid [13], which is reported to be catalysed mainly by UGT1A9 in the human liver [6]. Niflumic acid had a potent inhibitory effect on the glucuronidation of mycophenolic acid in human liver microsomes, and its IC 50 and K i values were 8 and 15 mm, respectively [13,14]. The affinities of niflumic acid and mycophenolic The substrate concentration of 4-methylumbelliferone was 5 mm.…”

Section: Discussionmentioning

confidence: 89%

In vitro inhibitory effects of non‐steroidal anti‐inflammatory drugs on 4‐methylumbelliferone glucuronidation in recombinant human UDP‐glucuronosyltransferase 1A9—potent inhibition by niflumic acid

Mano

Usui

Kamimura

2005

Biopharm & Drug Disp

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The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. 4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 microM. The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid. Niflumic acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 microM. The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Niflumic acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 microM, respectively, being similar to each IC50 value. In conclusion, of the seven NSAIDs investigated, niflumic acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner.

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“…proposed selective substrates and inhibitors of five major hepatic UGT isoforms and recommended inhibitor concentrations relative to their inhibition potency (IC 50 values). Examples of selective inhibitors are atazanavir for UGT1A1/1A3 (Zhang et al, 2005); hecogenin for UGT1A4 (Uchaipichat et al, 2006a,b;Walsky et al, 2012); troglitzone for UGT1A6 (Ito et al, 2001), digoxin, transilast, and niflumic acid for UGT1A9 (Vietri et al, 2002;Lapham et al, 2012); and b-phenyllongifolol-2 for 2B7 (Bichlmaier et al, 2007). Careful optimization of experimental conditions (Court, 2014;Zhou and Miners, 2014) (also more in Supplemental Materials) should be done for the selection of suitable inhibitor concentrations, e.g., when considering the presence of BSA, in particular for UGT1A9 and 2B7 reactions.…”

Section: Chemical Inhibitors Of Ugtmentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes

Cited by 19 publications

References 6 publications

An Investigation of Human and Rat Liver Microsomal Mycophenolic Acid Glucuronidation: Evidence for a Principal Role of Ugt1a Enzymes and Species Differences in Ugt1a Specificity

An Investigation of Human and Rat Liver Microsomal Mycophenolic Acid Glucuronidation: Evidence for a Principal Role of Ugt1a Enzymes and Species Differences in Ugt1a Specificity

In vitro inhibitory effects of non‐steroidal anti‐inflammatory drugs on 4‐methylumbelliferone glucuronidation in recombinant human UDP‐glucuronosyltransferase 1A9—potent inhibition by niflumic acid

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

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