| The absence of stereoselective P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum. | |
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MedLine Citation:
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PMID: 9720621 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (Peff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L(-1). The Peff of each enantiomer was also determined at 400 mg L(-1) when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of Peff from 0.42 x 10(-4) cm s(-1) to 0.80 x 10(-4) cm s(-1) (P < 0.05) at concentrations from 4 to 400 mg L(-1), respectively. The observed concentration-dependent jejunal Peff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal Peff increased to 1.47 x 10(-4) cm s(-1). There was no difference between the Peff of the two enantiomers in any of these experiments. The efflux of R/S-norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte. In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-norverapamil is formed inside the enterocytes. |
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Authors:
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R Sandström; A Karlsson; H Lennernäs |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The Journal of pharmacy and pharmacology Volume: 50 ISSN: 0022-3573 ISO Abbreviation: J. Pharm. Pharmacol. Publication Date: 1998 Jul |
Date Detail:
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Created Date: 1998-12-04 Completed Date: 1998-12-04 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376363 Medline TA: J Pharm Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 729-35 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, University of Uppsala, Sweden. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chlorpromazine / metabolism Intestinal Absorption Jejunum / metabolism* Male P-Glycoprotein / metabolism* Rats Stereoisomerism Vasodilator Agents / metabolism* Verapamil / analogs & derivatives, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/P-Glycoprotein; 0/Vasodilator Agents; 50-53-3/Chlorpromazine; 52-53-9/Verapamil; 67018-85-3/norverapamil |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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