Abstract:
:Earlier studies with etretinate and its metabolite acitretin suggested that area under the concentration-time curve (AUC) is the most suitable pharmacokinetic correlate to etretinate-induced teratogenesis. In an attempt to test this hypothesis with respect to the embryotoxic effects of all-trans-retinoic acid (all-trans-RA), we determined the embryotoxicity and plasma pharmacokinetics of all-trans-RA and its metabolites following administration of all-trans-RA to Wistar rats on Gestational Day (GD) 9, either subcutaneously (sc; dose levels 1, 3, or 5 mg/kg body mass) or orally (po; 5 mg/kg body mass). The 5 mg/kg dose of all-trans-RA was not embryotoxic when administered orally but led to high rates of embryolethality and skeletal defects following sc treatment. Determination of retinoids by HPLC showed that all-trans-RA reached similar maximum plasma concentrations (C(max)) after both dosing regimens, but its plasma AUC was ca. threefold higher after sc injection than po administration due to the slower uptake rate of the drug and its limited detoxification via beta-glucuronidation following sc injection. Furthermore, retinoid analysis in rat tissues (liver, kidney, duodenum, and jejunum), collected 1 hr after sc or po administration of 5 mg all-trans-RA/kg body mass on GD 9, confirmed that formation of all-trans-retinoyl-beta-glucuronide was much more extensive after po than after sc administration. Finally, linear regression analysis of either C(max). or AUC values of all-trans-RA in rat plasma and fetal abnormality rates showed that AUC values are better correlated with the embryotoxic outcome than C(max) [AUC-based correlation coefficient (r) > 0.90; C(max)-based r < 0.43]. Our findings establish the relevance of the AUC of all-trans-RA, and not its C(max), as the most appropriate pharmacokinetic marker of embryonic exposure and embryotoxic potency of all-trans-RA and stress the importance of the duration of exposure as a major determinant of embryotoxic outcome for retinoids.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Tzimas G,Thiel R,Chahoud I,Nau Hdoi
10.1006/taap.1997.8105subject
Has Abstractpub_date
1997-04-01 00:00:00pages
436-44issue
2eissn
0041-008Xissn
1096-0333pii
S0041-008X(97)98105-9journal_volume
143pub_type
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journal_title:Toxicology and applied pharmacology
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