Effect of inhalation anesthetics on antipyrine pharmacokinetics of mice

Dyke, Russell A. Van; Kooistra, Kimberly L.; Moses, C.Jill; Powis, Garth

doi:10.1016/0006-2952(87)90409-6

Cited by 5 publications

(1 citation statement)

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“…In the rat the clearance of orally administered antipyrine can be determined from a single saliva sample collected after stimulation with pilocarpine and this can probably be extended to metronidazole and the cocktail (Pilsgaard & Poulsen 1 W ) . Hence, anesthesia, surgical stress and indwelling catheters, which may all affect foreign compound metabolism, are avoided (Wood & Wood 1984, Van Dyke et al 1987Chindavijac et al 1988). With this simple non-invasive approach the animals could serve as their own control in paired designs and/or be characterized regarding five cytochrome P450 activities to relate to the toxicity or metabolism of other compounds.…”

Section: D Future Studies Of Metronidazole and Antipyrine Metabolismmentioning

confidence: 99%

Metronidazole and Antipyrine as Probes for the Study of Foreign Compound Metabolism

Loft

1990

Pharmacology & Toxicology

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The aim of the present work was to develop a tool for the study of the enzyme activities relevant for the biotransformation of foreign compounds, their elimination and/or activation to toxic substances. The activity of an enzyme may be assessed by the rate of metabolism of a preferably specific probe or model compound. The cytochrome P450'ies, the key enzymes for the elimination and/or activation of most foreign compounds, exist in multiple forms with variable substrate specificity and regulation. Some cytochrome P450'ies are under genetic control, whereas the activity of others is mainly regulated by the influence from factors in the environment. Only some of the cytochrome P450'ies are relevant for the formation of harmful metabolites. Thus, the activity of as many cytochrome P450 forms as possible should be assessable, preferably simultaneously. The present work evaluated metronidazole in a cocktail with antipyrine as a tool for the study of the regulation of foreign compound metabolism in the liver. The cytochrome P450 catalyzed metabolism of metronidazole and antipyrine was studied in humans and in isolated rat hepatocytes. In humans the influence of dose, route of administration, enzyme induction and inhibition and liver disease was investigated. Rats of either sex were studied with and without pretreatment with specific enzyme inducers and incubations included specific enzyme inhibitors. Evidence was provided that the oxidative formation of the five major metabolites, two from metronidazole and three from antipyrine, depends on different cytochrome P450'ies. In humans it was demonstrated that the clearance of metronidazole and antipyrine could be determined from the same saliva sample collected 16-24 hours after their oral administration and so could the clearance for formation of each metabolite if urine was collected for 48 hours. Thus, with the cocktail of metronidazole and antipyrine and simple non-invasive sampling the activity of five different cytochrome P450'ies can be assessed in vivo. In addition, metronidazole may also be used for assessment of the glucuronidation capacity although this is a minor pathway in man. Because the variation within subjects is much less than between them, the cocktail test is particularly suited for paired designs with measurements before and after an environmental change and the subjects serving as their own control. The metronidazole/antipyrine cocktail may have many applications in the study of the regulation of foreign compound metabolism in man and in animals, in vivo and in vitro.

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Section: D Future Studies Of Metronidazole and Antipyrine Metabolismmentioning

confidence: 99%