| No effect of phenobarbital pretreatment of rats on methotrexate pharmacokinetics in the isolated liver perfused in a single-pass way. | |
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MedLine Citation:
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PMID: 11174078 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pretreatment of the rat with phenobarbital (PB) is known to increase gene expression of the canalicular multispecific organic anion transporter (cMOAT) and hepatobiliary transport of its substrates (glutathione, sulfobromophthalein). To determine the effect of PB on the hepatobiliary transport of methotrexate (MTX, another substrate of cMOAT) and its metabolism to 7-hydroxymethotrexate (7-OHMTX) in the rat, we compared the steady-state pharmacokinetics of MTX in the isolated liver of either PB-pretreated (80 mg/day/kg bw for 4 days, i.p.) or nonpretreated rats. The livers were perfused in a single-pass way at a flow rate of 15 ml/min using a perfusate which consisted of Krebs-Henseleit buffer containing glucose, taurocholate, bovine albumin and erythrocytes. During the perfusion with 50 micromol/l MTX, the steady-state biliary clearance (1.26 +/- 0.24 ml/min) in 7 nonpretreated rats accounted for a major proportion of the hepatic clearance (1.30 +/- 0.33 ml/min), metabolism of MTX to 7- OHMTX was minor (partial metabolic clearance = 0.041 +/- 0.023 ml/min). MTX concentrations in bile surpassed those in the input perfusate by approximately 100-fold. Pretreatment of rats (n = 7) with PB did not change significantly the steady-state hepatic, biliary and partial metabolic clearances of 50 micromol/l MTX. An interesting result is a 38% increase in the hepatic vascular resistance of non-pretreated livers caused by MTX. The results suggest that in rats, pretreatment with PB has no effect on the hepatobiliary transport and hydroxylation of MTX. |
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Authors:
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J Chládek; J Martínková; L Sispera; J Chládková; J Cermanová |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Pharmacology Volume: 62 ISSN: 0031-7012 ISO Abbreviation: Pharmacology Publication Date: 2001 Feb |
Date Detail:
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Created Date: 2001-02-22 Completed Date: 2001-05-31 Revised Date: 2003-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0152016 Medline TA: Pharmacology Country: Switzerland |
Other Details:
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Languages: eng Pagination: 92-7 Citation Subset: IM |
Copyright Information:
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Copyright 2001 S. Karger AG, Basel. |
Affiliation:
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Department of Pharmacology, Faculty of Medicine, Charles University, Hradec Králové, Czech Republic. chladekj@lfhk.cuni.cz |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile / drug effects, secretion Excitatory Amino Acid Antagonists / pharmacology* Folic Acid Antagonists / pharmacokinetics* Liver / drug effects, metabolism* Male Methotrexate / analogs & derivatives, metabolism, pharmacokinetics* Oxygen Consumption / drug effects, physiology Phenobarbital / pharmacology* Rats Rats, Wistar Vascular Resistance / drug effects*, physiology |
| Chemical | |
Reg. No./Substance:
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0/Excitatory Amino Acid Antagonists; 0/Folic Acid Antagonists; 50-06-6/Phenobarbital; 59-05-2/Methotrexate; 5939-37-7/7-hydroxymethotrexate |
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