| Product inhibition and dose-dependent bioavailability of propranolol in the isolated perfused rat liver preparation. | |
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MedLine Citation:
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PMID: 7965671 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We investigated in the isolated perfused rat liver (IPRL) whether product inhibition of metabolism contributes to the dose-dependent bioavailability of propranolol, a drug with a high, but saturable, hepatic first-pass effect. (+/-)-Propranolol was infused in the IPRL, using a recirculating design, for three 36-min periods (n = 9). Mean steady-state reservoir, i.e. hepatic inflow concentrations (Cin), were 4.97, 10.4, and 20.4 microM, respectively. Mean reservoir concentrations of the metabolites 4'-hydroxypropranolol, 5'-hydroxypropranolol, N-desisopropylpropranolol, and naphthoxylactic acid (NLA), a major side-chain-oxidation metabolite, increased disproportionately with propranolol dose, but their production rate did not reach steady state. In separate experiments (n = 4), perfusate containing 7.1, 12.8, and 21.6 microM (+/-)-propranolol, corresponding to administration rates of 114, 205, and 346 nmol/min, respectively, was passed through the liver for 30 min each using a single-pass design. The bioavailability (hepatic outflow concentration/Cin) of propranolol increased with Cin from 0.012 to 0.150 to 0.288 in the recirculating IPRL. In the single-pass IPRL the increase (0.0077 in 0.0669 to 0.136) was significantly less (P < 0.001). The greater bioavailability of propranolol in recirculating experiments was attributed to product inhibition since metabolites do not accumulate with the single-pass design. NLA did not appear to be the inhibiting metabolite because in further single-pass experiments with propranolol Cin of 21.6 microM the presence of NLA (21.6 microM) in perfusate had no effect on propranolol bioavailability (n = 7) compared with control experiments (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS) |
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Authors:
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H Ghabrial; R Nand; C K Stead; R A Smallwood; D J Morgan |
Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of pharmaceutical sciences Volume: 83 ISSN: 0022-3549 ISO Abbreviation: J Pharm Sci Publication Date: 1994 Jul |
Date Detail:
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Created Date: 1994-12-02 Completed Date: 1994-12-02 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2985195R Medline TA: J Pharm Sci Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 931-6 Citation Subset: IM |
Affiliation:
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Department of Medicine, Repatriation Hospital, University of Melbourne, Victoria, Australia. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Availability Dose-Response Relationship, Drug Feedback / physiology Kinetics Liver / drug effects, metabolism* Liver Circulation / physiology Male Models, Biological Perfusion Propranolol / metabolism, pharmacokinetics* Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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525-66-6/Propranolol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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