Effects of non-steroid antirheumatic agents on microsomal drug-metabolizing enzymes of rat liver

Reinicke, C; Klinger, W

doi:10.1016/0006-2952(71)90267-x

Cited by 20 publications

(1 citation statement)

References 12 publications

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“…However, this new class of drugs carried risks for inducing hepatic and bone marrow toxicities resulting in decreased but persistent use in the clinic (Galati et al, 2002;Somchit et al, 2004;Goldkind and Laine, 2006;Narsinghani and Chaturvedi, 2006;Aronson, 2016). Unlike NSAID-induced gastrointestinal effects, few studies have been conducted to identify the mechanism for fenamate hepatotoxicity (Reinicke and Klinger, 1971;Wolfe et al, 1999;Galati et al, 2002;Somchit et al, 2004;Sriuttha et al, 2018). The proposed cause for this toxicity may arise from cytochromes P450 bioactivation of fenamates into reactive quinones that form adducts with hepatic proteins and glutathione (Galati et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

et al. 2020

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Meclofenamate is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain yet poses a rare risk of hepatotoxicity through an unknown mechanism. NSAID bioactivation is a common molecular initiating event for hepatotoxicity. Thus, we hypothesized a similar mechanism for meclofenamate and leveraged computational and experimental approaches to identify and characterize its bioactivation. Analyses employing our XenoNet model indicated possible pathways to meclofenamate bioactivation into 19 reactive metabolites subsequently trapped into glutathione adducts. We describe the first reported bioactivation kinetics for meclofenamate and relative importance of those pathways using human liver microsomes. The findings validated only four of the many bioactivation pathways predicted by modeling. For experimental studies, dansyl glutathione was a critical trap for reactive quinone metabolites and provided a way to characterize adduct structures by mass spectrometry and quantitate yields during reactions. Of the four quinone adducts, we were able to characterize structures for three of them. Based on kinetics, the most efficient bioactivation pathway led to the monohydroxy para-quinone-imine followed by the dechloro-ortho-quinone-imine. Two very inefficient pathways led to the dihydroxy ortho-quinone and a likely multiply adducted quinone. When taken together, bioactivation pathways for meclofenamate accounted for approximately 13% of total metabolism. In sum, XenoNet facilitated prediction of reactive metabolite structures while quantitative experimental studies provided a tractable approach to validate actual bioactivation pathways for meclofenamate. Our results provide a foundation for assessing reactive metabolite load more accurately for future comparative studies with other NSAIDs and drugs in general. Significance Statement Meclofenamate bioactivation may initiate hepatotoxicity yet common risk assessment approaches are often cumbersome and inefficient and yield qualitative insights that do not scale This article has not been copyedited and formatted. The final version may differ from this version.

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Section: Introductionmentioning

confidence: 99%

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

et al. 2020

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Effect of single and multiple treatments with phenylbutazone in normal and adjuvant-induced polyarthritic rats

DiPasquale¹,

Rassaert²,

Welaj³

et al. 1975

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Liver function alterations, in the adjuvant induced polyarthritis procedure in rats, has been demonstrated by many investigators. We observed a significant inhibition of the polyarthritis with phenylbutazone but we were unable to find any changes in the relative liver weights of SGPT, AP or BUN in polyarthritic or phenylbutazone treated rats. However, we did observe that polyarthritic rats maintained a significantly higher plasma phenylbutazone concentration than the corresponding non-arthritic controls. This appears to futher substantiate the influence of 'pathopharmacodynamics' on the disposition and activity of drugs.

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Salycylamide glucuronide formation in liver disease and its change by drugs

1975

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Salicylamide glucuronide (SAMG) in 0-6 and 6-12 hours-urine specimens was determined after oral administration of salicylamide in 7 normal volunteers (NV), in 51 cases of various liver diseases and hyperbilirubinemias, and in 19 cases after drug administration, to predict the in vivo drug metabolism in man and its change by drugs. Maximal glucuronide formation was obtained by 1.0 g of salicylamide administered to NV; thus, this dosage was used in the present study. SAMG as percent of total salicylamide, the percent of SAMG, from 0-6 hours-urine specimens was high and constant in NV (71.3 +/- 8.3 (Mean +/- S.D.)). 0-0.08% of the total salicylamide was confirmed as free salicylamide in 0-12 hours-urine specimens of NV. The percent of SAMG of 0-6 hours-urine specimens was 57.2 +/- 8.6 in acute hepatitis, 66.6 +/- 10.9 in chronic hepatitis, and 48.6 +/- 10.7 in liver cirrhosis (mean +/- S.D.). Free salicylamide increased slightly in liver diseases. Serum bilirubin levels tended to be inversely correlated with the percent of SAMG. In most cases of Gilbert's syndrome, the percent of SAMG remained at a normal level. The percent of SAMG in cases with unconjugated hyperbilirubinemias of other geneses were almost within normal limits. Bucolome and phenobarbital increased the percent of SAMG in patients with various liver diseases. After rifampicin or phenytoin administration, the percent of SAMG of the patients with lung tuberculosis or epilepsy did not surpass that of NV.

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Effects of non-steroid antirheumatic agents on microsomal drug-metabolizing enzymes of rat liver

Cited by 20 publications

References 12 publications

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics

Effect of single and multiple treatments with phenylbutazone in normal and adjuvant-induced polyarthritic rats

Salycylamide glucuronide formation in liver disease and its change by drugs

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