The effects of adjuvant-induced arthritis on the liver metabolism of drugs in rats

Morton, Duncan; Chatfield, David H.

doi:10.1016/0006-2952(70)90202-9

Cited by 72 publications

(13 citation statements)

References 13 publications

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“…The results of the present investigation very closely corroborate earlier findings both from indirect [ 11,15,20] and direct measurements [12][13][14][16][17][18][19] that liver microsomal enzyme activity responsible for drug metabolism is markedly reduced in rats with chronic inflammation, i.e., AIP. In our study this was observed indirectly by the marked prolongation of hexobarbital Na-induced sleeping time and extended to zoxazolamine-induced paralysis by Day 14 (Figs.…”

Section: Discussionsupporting

confidence: 95%

“…4 and 5). This correlates very well with the appearance of significant reductions in the activities of liver microsomal N-demethylase, NADPH2-oxidase and cytochrome P450 by Day 10 in AIP reported by MORTON and CHATFIELD [12].…”

Section: Discussionsupporting

confidence: 84%

“…MORTON and CHATFIELD [12] have shown that AIP rats, 15 days after induction of the disease, have a reduced capacity for oxidative metabolism, since the activities of cytochrome P450, N-demethylase and NADPH2-oxidase were reduced by 80%. They concluded that this phenomenon could theoretically have marked influence upon such parameters as the metabolic fate, half-life and toxicity of administered compounds.…”

Section: Introductionmentioning

confidence: 97%

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Alteration of hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation

1977

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Depression of the hepatic microsomal enzyme system(s) in adjuvant-induced polyarthritis (AIP), a chronic inflammation model, has been confirmed indirectly by the enhancement of hexobarbital Na-induced sleeping time and extended for the first time to zoxazolamine-induced paralysis. In addition, barbital Na-induced anesthesia was increased during the course of AIP development, indicating that the CNS of these rats appears to be more sensitive to drug effects, since this barbiturate is excreted virtually unmetabolized. Most likely because of these effects, LD50 values for acetylsalicylic acid, phenylbutazone and indomethacin in AIP rats decreased in terms of mg/kg (increased toxicity) as the disease became more severe (Day 21) since they are known ultimately to be metabolized by the liver. On the other hand, the toxicity of a new non-steroidal anti-inflammatory agent, meseclazone, was not altered significantly in AIP. This is most likely due to the fact that its near total conversion to 5-chlorosalicylic acid has been shown to occur by hydrolytic cleavage as it pases through the intestinal wall with litter hepatic involvement. Finally, carrageenan edema, a model of acute inflammation, did not affect barbiturate sleeping times of zoxazolamine paralysis, nor were any of these drugs studied more lethal in this disease state.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 97%

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Alteration of hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation

1977

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“…During the acute phase of AA-induced inflammation, prolonged sleep time has been reported for pentobarbital (Dipasquale et al, 1974) and hexobarbital (Baumgartner et al, 1974), possibly due to decreased drug metabolism. On the other hand, cytochrome P450 content appears to be unaltered at day 5 after adjuvant injection (Morton and Chatfield, 1970), and disposition of cyclosporine after 5 days of AA remains unaffected (Pollock et al, 1989). Our study showed a 48% reduction in total cytochrome P450 content on day 6 and corresponding decreases in verapamil intrinsic clearance.…”

Section: Effect Of Early Phase Aa On P450 Enzymes and Pk Of Verapamilmentioning

confidence: 99%

Effect of Early Phase Adjuvant Arthritis on Hepatic P450 Enzymes and Pharmacokinetics of Verapamil: An Alternative Approach to the Use of an Animal Model of Inflammation for Pharmacokinetic Studies

Ling

Jamali²

2005

Drug Metab Dispos

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ABSTRACT:The objective of this study was to evaluate the suitability of the early phase of adjuvant arthritis (pre-AA) as a model of inflammation for pharmacokinetic studies. Pre-AA is associated with little or no pain and discomfort as compared with fully developed adjuvant arthritis. Pre-AA was induced in male Sprague-Dawley rats with a tail base injection of Mycobacterium butyricum. Animals were monitored for symptoms of arthritis and levels of the proinflammatory mediators, serum nitrite, C-reactive protein (CRP), and tumor necrosis factor ␣ (TNF␣). On day 6, rats were administered single i.v. (2 mg/kg) or oral (20 mg/kg) doses of racemic verapamil, and S-and R-verapamil concentrations were determined by highperformance liquid chromatography. Hepatic cytochrome P450 (P450) content and verapamil protein binding were also measured. All experiments were carried out in both pre-AA and control rats. Serum nitrite, CRP, and TNF␣ levels were significantly elevated in pre-AA rats while signs of pain and arthritis were absent. Pre-AA also significantly elevated plasma concentrations of S-and Rverapamil after both i.v. and oral doses, due, likely, to decreased drug clearance. This was accompanied by a significant reduction in hepatic cytochrome P450, CYP3A, and CYP1A content as well as significantly reduced verapamil free fraction in pre-AA. The early phase of AA is marked by increased proinflammatory mediators and reduced verapamil clearance, as well as decreased hepatic P450 enzymes. Hence, pre-AA is a suitable model of inflammation for pharmacokinetic studies that avoids unnecessary exposure of animals to the pain and distress of fully developed adjuvant arthritis.

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“…The Mycobacterial component is 1) Inoculating adjuvants in susceptible rat strains engenders other pathologies, besides the arthropathy, which may profoundly affect drug action in vivo e.g. hypoalbuminemia, lesions in drug metabolism [8][9][10], altered drug sensitivity [8,9,11,12], tissue and cell fragility [13,14] and anemia (15).…”

mentioning

confidence: 99%

Standardisation of arthritogenic adjuvants for evaluating anti-inflammatory and immunosuppressant drugs

Whitehouse

Beck

1974

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The effects of adjuvant-induced arthritis on the liver metabolism of drugs in rats

Cited by 72 publications

References 13 publications

Alteration of hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation

Alteration of hepatic microsomal enzyme systems and the lethal action of non-steroidal anti-arthritic drugs in acute and chronic models of inflammation

Effect of Early Phase Adjuvant Arthritis on Hepatic P450 Enzymes and Pharmacokinetics of Verapamil: An Alternative Approach to the Use of an Animal Model of Inflammation for Pharmacokinetic Studies

Standardisation of arthritogenic adjuvants for evaluating anti-inflammatory and immunosuppressant drugs

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