Biotransformation of diclofenac sodium (Voltaren®) in animals and in man

Stierlin, H; Faigle, J. W.; Sallmann, A; Küng, W; Richter, Wilhelm J.; Kriemler, Hans-Peter; Alt, Karl O.; Winkler, Tammo

doi:10.3109/00498257909042327

Cited by 161 publications

(83 citation statements)

References 13 publications

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“…The hydroxylation of DF to 4OH-DF and 5OH-DF is catalyzed by CYP2C9 and CYP3A4, respectively (Tang, 2003). After glucuronidation, DF-AG can undergo further hydroxylation (Kumar et al, 2002), and hydroxylated DF-AG conjugates are major urinary metabolites (Stierlin et al, 1979).…”

Section: Diclofenac (Dfmentioning

confidence: 99%

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Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Lagas

Sparidans²,

Wagenaar³

et al. 2010

Mol Pharmacol

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Diclofenac is an important analgesic and anti-inflammatory drug that is widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Diclofenac is extensively metabolized in the liver, and the main metabolites are hydroxylated and/or glucuronidated conjugates. We show here that loss of multidrug resistance protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ ABCG2) in mice results in highly increased plasma levels of diclofenac acyl glucuronide, after both oral and intravenous administration. The absence of Mrp2 and Bcrp1, localized at the canalicular membrane of hepatocytes, leads to impaired biliary excretion of acyl glucuronides and consequently to elevated liver and plasma levels. Mrp2 also mediates the biliary excretion of two hydroxylated diclofenac metabolites, 4Ј-hydroxydiclofenac and 5-hydroxydiclofenac. We further show that the sinusoidal efflux of diclofenac acyl glucuronide, from liver to blood, is largely dependent on multidrug resistance protein 3 (MRP3/ABCC3). Diclofenac acyl glucuronides are chemically instable and reactive, and in patients, these metabolites are associated with rare but serious idiosyncratic liver toxicity. This might explain why Mrp2/Mrp3/Bcrp1(Ϫ/Ϫ) mice, which have markedly elevated levels of diclofenac acyl glucuronides in their liver, display acute, albeit very mild, hepatotoxicity. We believe that the handling of diclofenac acyl glucuronides by ATP binding cassette transporters may be representative for the handling of acyl glucuronide metabolites of many other clinically relevant drugs.

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Section: Diclofenac (Dfmentioning

confidence: 99%

“…When given orally, absorption is rapid and complete (Stierlin et al, 1979;Peris-Ribera et al, 1991;Davies and Anderson, 1997). The metabolism of DF partitions between acyl glucuronidation and aryl hydroxylation (Tang, 2003), and the major metabolites are DF acyl glucuronide (DF-AG), 4Ј-hydroxy DF (4OH-DF), and 5-hydroxy DF (5OH-DF; Fig.…”

Section: Diclofenac (Dfmentioning

confidence: 99%

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Lagas

Sparidans²,

Wagenaar³

et al. 2010

Mol Pharmacol

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“…These observations have major implications for lead optimization for drugs metabolized by UGTs and for predicting human PK from preclinical data. b Clinical f m,UGT values were obtained from the literature as follows: ketoprofen, zidovudine, and gemfibrozil (Kilford et al, 2009); imipramine and furosemide (Soars et al, 2002); lorazepam (Greenblatt, 1981); levofloxacin (Fish and Chow, 1997); diclofenac (Stierlin et al, 1979); raloxifene and mycophenolic acid (Cubitt et al, 2009); and indomethacin (Duggan et al, 1972). …”

Section: Animal Scale-up Of Ugt Substratesmentioning

confidence: 99%

Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

Deguchi¹,

Watanabe²,

Kurihara³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The aim of the current study was to evaluate the accuracy of allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions were conducted from preclinical in vivo data by using multiple-species allometry with the rule of exponents and single-species allometric scaling (SSS) of mice, rats, monkeys, or dogs. Distribution volume at a steady state (V ss ) was predicted by multiple-species allometry or SSS of V ss . Oral plasma clearance (CL po ) was calculated under the assumption that F a ؋ F g was equivalent across species. Each of the results was compared with the observed parameter calculated from the clinical data after intravenous or oral administration. Multiple-species allometry and SSS of mice, rats, and dogs resulted in a similar accuracy of CL and CL po predictions. Monkeys tended to provide the most accurate predictions of human CL and CL po . The ability to predict the half-life, which was determined from CL and V ss predictions, was more accurate in SSS of rats and monkeys. The in vivo fraction metabolized by glucuronidation (f m,UGT ) in bile duct-cannulated monkeys was relatively similar to that of humans compared with other animal species, which likely contributed to the highest accuracy of SSS prediction of monkeys. On the basis of the current results, monkeys would be more reliable than other animal species in predicting human pharmacokinetics and f m,UGT for drugs metabolized by UGTs.

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“…Metabolites of diclofenac were detected based on their MS and product ion spectra obtained by positive ion electrospray with data-dependent MS/MS. The identity of 4Ј-hydroxy-diclofenac (Stierlin et al, 1979) was confirmed by comparison with an authentic standard.…”

Section: Et Almentioning

confidence: 84%

Metabolite Generation via Microbial Biotransformations with Actinomycetes: Rapid Screening for Active Strains and Biosynthesis of Important Human Metabolites of Two Development-Stage Compounds, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101) and Dasatinib

Li¹,

Josephs²,

Skiles³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The enzymes present in many microbial strains are capable of carrying out a variety of biotransformations when presented with drug-like molecules. Although the enzymes responsible for the biotransformations are not well characterized, microbial strains can often be found that produce metabolites identical to those found in mammalian systems. However, traditional screening for microbial strains that produce metabolites of interest is done with many labor intensive steps that include multiple shake flasks and many manual manipulations, which hinder the application of these techniques in drug metabolite preparation. A 24-well microtiter plate screening system was developed for rapid screening of actinomycetes strains for their ability to selectively produce metabolites of interest. The utility of this system was first demonstrated with the well characterized cytochrome P450 substrate diclofenac. Subsequently, the use of this system allowed the rapid identification of several actinomycetes strains that were capable of converting two drug candidates under development, 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic acid and N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, Sprycel, BMS-345825), to mammalian metabolites of interest. Milligram quantities of the metaboliteswere then prepared by scaling-up the microbial biotransformation reactions. These quantities were sufficient for initial characterization, such as testing for pharmacological activity and use as analytical standards, prior to the availability of authentic chemically synthesized compounds.An integral part of the drug discovery and development process involves characterization of the metabolites of a drug candidate. The major purposes of these characterizations are to: 1) help ensure that human metabolites are adequately tested in toxicology species, 2) determine whether any of the pharmacological activity of the drug is due to active metabolites, and 3) aid in the determination of the mechanism of metabolic clearance of the parent drug (Baillie et al., 2002; http://www.fda. gov/cder/guidance). Standard testing paradigms for ensuring the safety of drug metabolites have been recently proposed, and aspects of these proposals were recently reviewed (Davis-Bruno and Atrakchi, 2006;Guengerich, 2006;Humphreys and Unger, 2006;Smith and Obach, 2006; http://www.fda.gov/cder/guidance). Considerable effort is often required to prepare sufficient quantities of key mammalian metabolites of drug candidates for biological activity evaluation or for use as analytical standards. Metabolite biosynthesis methods using mammalian systems (microsomes, S9, hepatocytes, in vivo, etc.) are useful for generating limited quantities of metabolites for structure elucidation by LC/MS/MS and NMR analysis. Chemical synthesis is the preferred method for larger scale metabolite preparation, but it is often ...

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Biotransformation of diclofenac sodium (Voltaren®) in animals and in man

Cited by 161 publications

References 13 publications

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Hepatic Clearance of Reactive Glucuronide Metabolites of Diclofenac in the Mouse Is Dependent on Multiple ATP-Binding Cassette Efflux Transporters

Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

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