Retinoid teratogenicity in the macaque: Verification of dosing regimen

Citation
Ag. Hendrickx et al., Retinoid teratogenicity in the macaque: Verification of dosing regimen, J MED PRIM, 27(6), 1998, pp. 310-318
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Animal Sciences","Animal & Plant Sciences
Journal title
JOURNAL OF MEDICAL PRIMATOLOGY
ISSN journal
0047-2565 → ACNP
Volume
27
Issue
6
Year of publication
1998
Pages
310 - 318
Database
ISI
SICI code
0047-2565(199812)27:6<310:RTITMV>2.0.ZU;2-N
Abstract
To further define teratogenicity associated with 13-cis-retinoic acid (13-c is-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestation al day [GD] 12-27, n = 11) investigated the teratogenicity of a single dail y dose of 13-cis-RA administered shortly after embryo implantation. Pharmac okinetic sampling was done to determine retinoid profiles on the first (GD1 2) and last (GD27) days of treatment. Exposure to 13-cis-RA during early or ganogenesis in Exp. 2 (2.5 mg/kg/day, GD20-27, and 2 x 2.5 mg/kg/day, GD28- 30, n = 5) investigated the potential adverse effects of 13-cis-RA on the d eveloping limb. The use of multiple doses of 13-cis-RA in Exp, 3 (2 x 2.5 m g/kg/day, GD26-27, n = 5) investigated the necessity of double dosing on th e induction of retinoid embryopathy in the macaque. Malformations of retino id target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogen esis in Exp. 1. Moreover, multiple doses on GD26-27 failed to induce any ma nifestation of abnormal development in Exp. 3. These results confirm that t he lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather t han 5.0 times greater than that observed in human pregnancies. Exposure dur ing forelimb development (GD20-30) in Exp. 2 was unsuccessful in inducing d efects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure t o the administered drug and its 4-oxo-metabolite. Zn contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriat e model for characterizing the teratogenic potential of retinoids in humans .