PMID- 10203012
OWN - NLM
STAT- MEDLINE
DCOM- 19990601
LR  - 20191103
IS  - 0047-2565 (Print)
IS  - 0047-2565 (Linking)
VI  - 27
IP  - 6
DP  - 1998 Dec
TI  - Retinoid teratogenicity in the macaque: verification of dosing regimen.
PG  - 310-8
AB  - To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) 
      in the cynomolgus monkey, the drug was orally administered on three different 
      treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 
      12-27, n = 11) investigated the teratogenicity of a single daily dose of 
      13-cis-RA administered shortly after embryo implantation. Pharmacokinetic 
      sampling was done to determine retinoid profiles on the first (GD12) and last 
      (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis 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 developing limb. 
      The use of multiple doses of 13-cis-RA in Exp. 3 (2 x 2.5 mg/kg/day, GD26-27, n = 
      5) investigated the necessity of double dosing on the induction of retinoid 
      embryopathy in the macaque. Malformations of retinoid target organs as well as 
      embryolethality were most prevalent when single daily doses of 13-cis-RA were 
      administered during pre- and early organogenesis in Exp. 1. Moreover, multiple 
      doses on GD26-27 failed to induce any manifestation of abnormal development in 
      Exp. 3. These results confirm that the lowest observed adverse effect level 
      (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in 
      human pregnancies. Exposure during forelimb development (GD20-30) in Exp. 2 was 
      unsuccessful in inducing defects 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 to the administered drug and its 4-oxo-metabolite. In 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 
      appropriate model for characterizing the teratogenic potential of retinoids in 
      humans.
FAU - Hendrickx, A G
AU  - Hendrickx AG
AD  - California Regional Primate Research Center, University of California, Davis 
      95616, USA.
FAU - Tzimas, G
AU  - Tzimas G
FAU - Korte, R
AU  - Korte R
FAU - Hummler, H
AU  - Hummler H
LA  - eng
GR  - RR00169/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Denmark
TA  - J Med Primatol
JT  - Journal of medical primatology
JID - 0320626
RN  - 0 (Retinoids)
SB  - IM
MH  - *Abnormalities, Drug-Induced
MH  - Animals
MH  - Drug Administration Schedule
MH  - Female
MH  - Fetus/*drug effects
MH  - Macaca fascicularis/abnormalities/*embryology
MH  - Pregnancy
MH  - Pregnancy, Animal/*drug effects
MH  - Retinoids/administration & dosage/*toxicity
EDAT- 1999/04/15 00:00
MHDA- 1999/04/15 00:01
CRDT- 1999/04/15 00:00
PHST- 1999/04/15 00:00 [pubmed]
PHST- 1999/04/15 00:01 [medline]
PHST- 1999/04/15 00:00 [entrez]
AID - 10.1111/j.1600-0684.1998.tb00081.x [doi]
PST - ppublish
SO  - J Med Primatol. 1998 Dec;27(6):310-8. doi: 10.1111/j.1600-0684.1998.tb00081.x.