Biotransformation of Diclofenac Sodium (Voltaren®) in Animals and in Man.: II. Quantitative determination of the unchanged drug and principal phenolic metabolites, in urine and bile

Stierlin, H; Faigle, J. W.

doi:10.3109/00498257909042328

Cited by 121 publications

(52 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…hepatic circulation of NSAIDs and their metabolites (2,9,29). The gastric and duodenal or ileal damage caused by NSAID toxicity are explained by different factors such as acid and pepsin or intestinal bacteria, respectively (3,26).…”

mentioning

confidence: 99%

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

Uejima

Kinouchi

Kataoka

et al. 1996

Microbiology and Immunology

View full text Add to dashboard Cite

The role of intestinal bacteria in induction and repression of ulcer formation in the ileum of rats treated with one of the nonsteroidal antiinflammatory drugs (NSAIDs), 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), was examined in this study. BFMeT was administered by intragastric gavage once at doses of 500-1,500 mg/kg of body weight to Wistar rats treated with and without antibiotics (bacitracin, neomycin, streptomycin), germ-free rats and gnotobiotic rats, and 72 hr later their gastrointestinal tracts were examined for ulcer formation. A single oral administration of BFMeT induced ileal ulcers in specific pathogen-free rats. However, the rats given antibiotics to reduce the intestinal bacteria had no ulcers. BFMeT-treated germ-free rats and gnotobiotic rats mono-associated with Bifidobacterium adolescentis or Lactobacillus acidophilus also had no intestinal ulcers. However, the drug induced ileal ulcers in gnotobiotic rats mono-associated with Eubacterium limosum or Escherichia coli. An overnight culture of B. adolescentis or L. acidophilus or yogurt containing Bifidobacterium breve and Streptococcus thermophilus, when given as drinking water, inhibited ulcer formation in the ileum of rats treated with BFMeT. Gram staining of the ileal contents of normal rats revealed that 97.4% of the stained microorganisms were Gram-positive rods and only 1.2 % were Gram-negative rods. In the group of rats with ulcers induced by BFMeT, the Gram-positive rods decreased by 56.4% and the Gram-negative rods including Escherichia coli, Klebsiella, Proteus and Bacteroides increased by 37.3%. However, in the group of rats administered the Bifidobacterium culture, the Lactobacillus culture or yogurt, the percentages of the Gram-negative rods were decreased. Although Lactobacillus was a major bacterium in the ileum of normal rats, the Gram-negative facultatively anaerobic rods E. coli, Klebsiella and Proteus were increased in the ulcerated ileum of rats treated with BFMeT, suggesting that these bacteria are associated with ulcer formation in rats treated with NSAIDs, and that Lactobacillus and Bifidobacterium inhibit it by repressing the growth of ulcer-inducing bacteria.

show abstract

mentioning

confidence: 99%

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

Uejima

Kinouchi

Kataoka

et al. 1996

Microbiology and Immunology

View full text Add to dashboard Cite

show abstract

“…The NSAIDs are eliminated from the body mainly by the liver by biliary excretion and metabolism including glucuronidation in rats (Yesair et al, 1970;Sumner et al, 1975;Stierlin and Faigle, 1979;Cayen et al, 1981;Foster and Jamali, 1988;Dietzel et al, 1990;Iwakawa et al, 1991) except salicylate and sulindac. For salicylate, the renal and hepatic elimination occurs to a similar degree (Yue and Varma, 1982).…”

Section: Discussionmentioning

confidence: 99%

FUNCTIONAL INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 2 (SLC22A7) IN THE HEPATIC UPTAKE OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG KETOPROFEN

Morita¹,

Kusuhara²,

Nozaki³

et al. 2005

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Rat organic anion transporter 2 (rOat2, Slc22a7) is a sinusoidal multispecific organic anion transporter in the liver. The role of rOat2 in the hepatic uptake of drugs has not been thoroughly investigated yet. rOat2 substrates include nonsteroidal anti-inflammatory drugs, such as ketoprofen, indomethacin, and salicylate. In the present study, the uptake of ketoprofen, indomethacin, and salicylate by freshly isolated rat hepatocytes was characterized. The uptake of ketoprofen, indomethacin, and salicylate by hepatocytes was sodium-independent, and the rank order of their uptake activities was indomethacin > ketoprofen > salicylate. Kinetic analysis based on Akaike's Information Criterion suggested that the uptake of ketoprofen and indomethacin by hepatocytes consists of two saturable components and one nonsaturable one. The K m and V max values for the high-and low-affinity components for ketoprofen uptake were 0.84 and 97 M and 35 and 1800 pmol/ min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 M and 130 and 16,000 pmol/min/mg protein, respectively. The K m values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 M for ketoprofen and indomethacin, respectively). The uptake of ketoprofen by hepatocytes was significantly inhibited by probenecid and rOat2 inhibitors (indocyanine green, indomethacin, glibenclamide, and salicylate). Other inhibitors of rOatps (taurocholate and pravastatin) and rOat3 (pravastatin and p-aminohippurate) had a slight effect, but digoxin had no effect. These results suggest that rOat2 accounts partly for the hepatic uptake of ketoprofen and, presumably, indomethacin as a high-affinity site and that other transporters, such as rOatps, but not rOatp2, and rOat3, are also involved.

show abstract

“…Any attempt to deconstruct protein haptenation by carboxylate drugs in vivo must differentiate between adduction products, some with identical substructures, of multiple bioactivation pathways: oxidation (Kenny et al, 2004), thioesterification (Grillo et al, 2003), and acyl glucuronylation (Stierlin and Faigle, 1979). Thioester and AG metabolites will produce indistinguishable N-acyl adducts (Skonberg et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Hammond

Meng

Jenkins

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.

show abstract

Biotransformation of Diclofenac Sodium (Voltaren®) in Animals and in Man.: II. Quantitative determination of the unchanged drug and principal phenolic metabolites, in urine and bile

Cited by 121 publications

References 3 publications

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

FUNCTIONAL INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 2 (SLC22A7) IN THE HEPATIC UPTAKE OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG KETOPROFEN

Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Contact Info

Product

Resources

About