| Isotretinoin (13-cis-retinoic acid) metabolism, cis-trans isomerization, glucuronidation, and transfer to the mouse embryo: consequences for teratogenicity. | |
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MedLine Citation:
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PMID: 1677495 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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It has been reported that fractionated doses of 13-cis-retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 x 100 mg/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and/or its metabolites. The major plasma metabolite of 13-cis-retinoic acid in the mouse was 13-cis-retinoyl-beta-glucuronide, followed by the 4-oxo metabolites and all-trans-retinoic acid. Transfer to the mouse embryo was very efficient for all-trans-retinoic acid, whereas, it was tenfold less efficient for 13-cis-retinoic acid and 100-fold less efficient for 13-cis-retinoyl-beta-glucuronide. The isomer all-trans-retinoic acid was found in the placenta at concentrations two- to three-fold higher than in the plasma, suggesting placental accumulation as well as placental cis/trans isomerization. Since 13-cis-retinoyl-beta-glucuronide and 13-cis- and all-trans-retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all-trans-retinoic acid, a well-known potent teratogen detected at concentrations of between 590 and 80 ng/g for 10 critical hours during gestation, could have been the major component. |
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Authors:
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J Creech Kraft; C Eckhoff; D M Kochhar; G Bochert; I Chahoud; H Nau |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Teratogenesis, carcinogenesis, and mutagenesis Volume: 11 ISSN: 0270-3211 ISO Abbreviation: Teratog., Carcinog. Mutagen. Publication Date: 1991 |
Date Detail:
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Created Date: 1991-08-28 Completed Date: 1991-08-28 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8100917 Medline TA: Teratog Carcinog Mutagen Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 21-30 Citation Subset: IM |
Affiliation:
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Institute of Toxicology and Embryopharmacology, Free University Berlin, Federal Republic of Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Bone and Bones / abnormalities, drug effects Drug Administration Schedule Embryo, Mammalian / drug effects* Female Gestational Age Glucuronates / blood, metabolism* Isotretinoin / pharmacokinetics* Maternal-Fetal Exchange / drug effects Mice Mice, Inbred Strains Placenta / chemistry, drug effects Pregnancy Stereoisomerism Teratogens* Tretinoin / administration & dosage, analogs & derivatives*, toxicity |
| Grant Support | |
ID/Acronym/Agency:
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HD 20925/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glucuronates; 0/Teratogens; 302-79-4/Tretinoin; 401-10-5/retinoyl glucuronide; 4759-48-2/Isotretinoin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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