Isotretinoin (13‐cis‐retinoic acid) metabolism,cis‐transisomerization, glucuronidation, and transfer to the mouse embryo: Consequences for teratogenicity
作者:
J. Creech Kraft,
Chr. Eckhoff,
D. M. Kochhar,
G. Bochert,
I. Chahoud,
H. Nau,
期刊:
Teratogenesis, Carcinogenesis, and Mutagenesis
(WILEY Available online 1991)
卷期:
Volume 11,
issue 1
页码: 21-30
ISSN:0270-3211
年代: 1991
DOI:10.1002/tcm.1770110104
出版商: Wiley Subscription Services, Inc., A Wiley Company
关键词: placental transfer;teratogen;embryotoxic;pharmacokinetic profiles;plasma metabolite
数据来源: WILEY
摘要:
AbstractIt 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 × 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‐β‐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‐β‐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 placentalcis/transisomerization. Since 13‐cis‐retinoyl‐β‐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 fo
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