| Oxygen dependence of salbutamol elimination by the isolated perfused rat liver. | |
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MedLine Citation:
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PMID: 2719719 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Although impairment of drug metabolism by severe hypoxia is well documented in perfused liver preparations, the degree of hypoxia required to produce inhibition of drug elimination pathways in the intact liver has not been defined. In this study, in the isolated perfused rat liver, we examined the relationship between the rate of hepatic oxygen supply and the elimination rate of the drug salbutamol, which in the rat liver is eliminated largely by glucuronidation. Livers (N = 15) from male Sprague-Dawley rats were perfused in a non-recycling design with 10% human red cells in a Krebs-Henseleit electrolyte solution. Salbutamol elimination was examined during normal oxygenation (perfusate equilibrated with 100% O2; mean O2 delivery 3.21 mumol/min/g liver), at a given lower rate of oxygen delivery (achieved by producing different mixtures of N2 with O2 in the perfusate oxygenator) and after reoxygenation. In these experiments, hepatic clearance of salbutamol (perfusate concentration 50 ng/ml) was essentially independent of oxygen delivery above a rate of 2.0 mumol/min/g liver; below this level, clearance fell linearly as O2 supply was reduced. In all livers, reoxygenation restored drug elimination to control levels. In further experiments using a recycling design (N = 22), the effect of hypoxia on salbutamol elimination was found to be very similar. In recycling normoxic experiments (N = 3), the glucuronide metabolite was detected in perfusate and bile, but no sulphate metabolite was detected. While previous studies indicate that elimination of some oxidatively metabolised substrates is very sensitive to reductions in hepatic oxygenation, the present study shows that, in the isolated liver, large reductions in hepatic oxygen supply were required to produce significant impairment of the glucuronidation-dependent elimination of salbutamol. |
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Authors:
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P W Angus; G W Mihaly; D J Morgan; R A Smallwood |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemical pharmacology Volume: 38 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1989 May |
Date Detail:
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Created Date: 1989-06-12 Completed Date: 1989-06-12 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 1443-9 Citation Subset: IM |
Affiliation:
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University of Melbourne Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Albuterol
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pharmacokinetics* Animals Glucuronates / metabolism Half-Life Liver / metabolism* Male Metabolic Clearance Rate Oxygen / pharmacology* Oxygen Consumption Perfusion Rats Rats, Inbred Strains |
| Chemical | |
Reg. No./Substance:
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0/Glucuronates; 18559-94-9/Albuterol; 7782-44-7/Oxygen |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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