Influence of non-steroid anti-inflammatory drugs (NSAIDs) on hepatic tyrosine aminotransferase (TA) activity in rats in vitro and in vivo

Reinicke, C

doi:10.1016/0006-2952(75)90276-2

Cited by 7 publications

(2 citation statements)

References 31 publications

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“…A metabolic product common to both drugs may be the active principal but, in accord with the binding data, it would have to be formed in vitro. IDM is also known to result in salt and water retention (3) (32). Perhaps the greatest difficulty with this hypothesis is reconciling the structural differences between NSAID and steroids.…”

Section: In Vitro Mineralocorticoid Binding Studies Nsaidmentioning

confidence: 99%

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Feldman¹,

Couropmitree²

1976

J. Clin. Invest.

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A B S T R A C T Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone > spironolactone > phenylbutazone (PBZ) > aspirin (ASA) > indomethacin (IDM). Concentration ratios required to obtain significant displacement of ['H]aldosterone were high but clearly within the therapeutic range for PBZ and ASA but not IDM. The analogues oxyphenbutazone (OBZ) and sodium salicylate (SS) were similar in binding activity to PBZ and ASA, respectively. Lineweaver-Burk analysis revealed that the inhibition of [8H]aldosterone binding was competitive in nature. In addition, PBZ was shown to prevent the nuclear binding of ['H]aldosterone.In vivo injection of PBZ and ASA resulted in competition for [8H]aldosterone renal binding comparable to the in vitro studies. Administration of PBZ and OBZ to adrenalectomized rats resulted in significant salt retention whereas ASA and SS did not differ significantly from controls. Salt retention elicited by PBZ and OBZ was inhibited by spironolactone, a competitive mineralocorticoid antagonist. These data suggest that, despite nonsteroidal structures, PBZ and OBZ induce salt retention via a receptor-mediated mineralocorticoid pathway analogous to aldosterone action.

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Section: In Vitro Mineralocorticoid Binding Studies Nsaidmentioning

confidence: 99%

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Feldman¹,

Couropmitree²

1976

J. Clin. Invest.

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“…In addition, Falzon et al Π/ have shown that inhibition of microsomal NADH-cytochrome b 5 reductase, cytochrome P-450 monooxygenases and epoxide hydrolase by high concentrations of indomethacin in vitro may be a function of the detergent properties of the drug. Although detergent effects may account for some of the loss of cytochrome P-450 at pharmacological doses of indomethacin in rats /8/, this property is probably not responsible for adverse effects at therapeutic doses.…”

Section: Introductionmentioning

confidence: 97%

Flavoenzymes Inhibited by Indomethacin

Chen¹,

Raybuck²,

Ziegler³

1994

Drug Metabolism and Drug Interactions

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The effect of indomethacin on the activity of five different flavoenzymes, three dehydrogenases and six hydrosases, was determined. Indomethacin at concentration 1.0 mM inhibited the activity, in decreasing order of sensitivity, of the following flavoenzymes: D-amino acid oxidase (pig kidney), flavin-containing monooxygenases (pig liver microsomal), cyclohexanone monooxygenase (Acinetobacter), NADPH-quinone reductase (pig liver), and glutathione reductase (yeast), but it had no effect on the activity of glucose oxidase (Aspergillus) or liver microsomal NADPH-cytochrome P-450 reductase. Indomethacin was competitive with D-alanine for the D-amino acid oxidase (Ki=30 microM) and with NADPH for all other flavoenzymes sensitive to this compound (Kis 170-500 microM). While indomethacin also inhibited two of the three NAD(P)+-dependent dehydrogenases tested, the Kis were relatively high (<1, 500 microM), and of the six different hydrolases tested only one, liver microsomal esterase, was inhibited by indomethacin (Ki=600 microM). Indomethacin also inhibited aminopyrine demethylation catalyzed by the liver microsomal P-450 monooxygenase (Ki=1,000 microM). Although the exact mechanism for the inhibition of functionally different flavoenzymes sensitive to indomethacin is not known, the inhibition is probably not due to the detergent properties of this drug.

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Screening and Assessment of the Potency of Anti-Inflammatory Drugs in vitro

Gryglewski¹

1979

Handbook of Experimental Pharmacology

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Influence of non-steroid anti-inflammatory drugs (NSAIDs) on hepatic tyrosine aminotransferase (TA) activity in rats in vitro and in vivo

Cited by 7 publications

References 31 publications

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Flavoenzymes Inhibited by Indomethacin

Screening and Assessment of the Potency of Anti-Inflammatory Drugs in vitro

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