EMAIL THIS PAGE TO A FRIEND

Archives of toxicology

Diclofenac toxicity in human intestine ex vivo is not related to the formation of intestinal metabolites.


PMID 24770551

Abstract

The use of diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is associated with a high prevalence of gastrointestinal side effects. In vivo studies in rodents suggested that reactive metabolites of DCF produced by the liver or the intestine might be responsible for this toxicity. In the present study, precision-cut intestinal slices (PCIS) prepared from the jejunum of 18 human donors were used as an ex vivo model to investigate whether DCF intestinal metabolites are responsible for its intestinal toxicity in man. PCIS were incubated with a concentration range of DCF (0-600 µM) up to 24 h. DCF (≥400 µM) caused direct toxicity to the intestine as demonstrated by ATP depletion, morphological damage, caspase 3 activation, and lactate dehydrogenase leakage. Three main metabolites produced by PCIS (4'-hydroxy DCF, 5-hydroxy DCF, and DCF acyl glucuronide) were detected by HPLC. Protein adducts were detected by immunohistochemical staining and showed correlation with the intestinal metabolites. DCF induced similar toxicity to each of the samples regardless of the variation in metabolism among them. Less metabolites were produced by slices incubated with 400 µM DCF than with 100 µM DCF. The addition of the metabolic inhibitors such as ketoconazole, cimetidine, or borneol decreased the metabolite formation but increased the toxicity. The results suggest that DCF can induce intestinal toxicity in human PCIS directly at therapeutically relevant concentrations, independent of the reactive metabolites 4'-OH DCF, 5-OH DCF, or diclofenac acylglucuronide produced by the liver or formed in the intestine.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

09735
Ammonium formate, BioUltra, ≥99.0% (calc. based on dry substance, NT)
CH5NO2
70221
Ammonium formate, eluent additive for LC-MS, LiChropur, ≥99.0%
CH5NO2
C4522
Cimetidine
C10H16N6S
PHR1075
Cimetidine, Pharmaceutical Secondary Standard; Certified Reference Material
C10H16N6S
C2175000
Cimetidine, European Pharmacopoeia (EP) Reference Standard
C10H16N6S
1134062
Cimetidine, United States Pharmacopeia (USP) Reference Standard
C10H16N6S
Y0001130
Cimetidine for peak identification, European Pharmacopoeia (EP) Reference Standard
C10H16N6S
Y0001146
Cimetidine for system suitability, European Pharmacopoeia (EP) Reference Standard
C10H16N6S
Y0001635
Diclofenac for system suitability, European Pharmacopoeia (EP) Reference Standard
C14H10Cl2NNaO2
S0765000
Diclofenac sodium, European Pharmacopoeia (EP) Reference Standard
C14H10Cl2NNaO2
1188800
Diclofenac sodium, United States Pharmacopeia (USP) Reference Standard
C14H10Cl2NNaO2
D6899
Diclofenac sodium salt
C14H10Cl2NNaO2
93484
Diclofenac sodium salt, analytical standard
C14H10Cl2NNaO2
PHR1144
Diclofenac sodium salt, Pharmaceutical Secondary Standard; Certified Reference Material
C14H10Cl2NNaO2
K1003
Ketoconazole, 99.0-101.0% (EP, titration)
C26H28Cl2N4O4
PHR1385
Ketoconazole, Pharmaceutical Secondary Standard; Certified Reference Material
C26H28Cl2N4O4
1356508
Ketoconazole, United States Pharmacopeia (USP) Reference Standard
C26H28Cl2N4O4
K0600000
Ketoconazole, European Pharmacopoeia (EP) Reference Standard
C26H28Cl2N4O4
UC280
Ketoconazole
C26H28Cl2N4O4