PMID- 7871482
OWN - NLM
STAT- MEDLINE
DCOM- 19950330
LR  - 20131121
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 50
IP  - 3
DP  - 1994 Sep
TI  - Maternal toxicokinetics, metabolism, and embryo exposure following a teratogenic 
      dosing regimen with 13-cis-retinoic acid (isotretinoin) in the cynomolgus monkey.
PG  - 184-93
AB  - The maternal pharmacokinetics, metabolism, and placental transfer of 
      13-cis-retinoic acid (isotretinoin) have been determined in the cynomolgus monkey 
      using a dosing regimen which had been previously shown to result in 
      retinoid-specific teratogenic effects [Hummler et al. (1990) Teratology 
      42:263-272]. The drug (2.5 mg/kg body weight) was administered by nasogastric 
      intubation once a day between gestational days (GD) 16-26, and twice a day 
      between GD 27-31. Maternal plasma kinetics were determined following dosing on GD 
      26 and GD 31, and placental transfer was studied following the last dose on GD 
      31. The plasma half life of 13-cis-retinoic acid in the monkey (13.2 h) was 
      comparable to that in the human. The main plasma metabolite in the monkey was the 
      13-cis-4-oxo-retinoic acid which occurred at levels lower or comparable to those 
      of the administered drug. During multiple dosing, this metabolite accumulated to 
      the same degree as the parent drug. All-trans-retinoic acid was present in 
      maternal plasma in very low concentrations (2% of 13-cis-retinoic acid). The 
      beta-glucuronides of all-trans- and 13-cis-retinoic acid were further minor 
      plasma metabolites. 13-cis-retinoic acid and its 4-oxo-metabolite reached the 
      monkey embryo slowly but extensively during organogenesis and reached 24 h-AUC 
      values of 956 and 590 ng.h/g embryo wet weight, resulting in embryo/maternal 
      plasma concentration ratios of 0.41 and 0.33, respectively. The AUC value of 
      all-trans-retinoic acid (316 ng.h/g) was only raised approximately 40% above the 
      endogenous AUC level (225 ng.h/g); only at two time periods examined were the 
      embryonic all-trans-retinoic acid concentrations above endogenous levels (at 4 h 
      and 8 h; P < 0.01 and < 0.05, respectively; Student's t-test). The 
      beta-glucuronides of all-trans- and 13-cis-retinoic acid were not detected in the 
      embryo. Accumulation of 13-cis-retinoic acid and the 4-oxo-metabolite during the 
      twice-per-day dosing regimen was apparent both in maternal plasma and embryo. An 
      interspecies comparison suggests that the half life as well as the metabolic 
      pattern of 13-cis-retinoic acid in plasma were similar in monkey and human: 
      13-cis-4-oxo-retinoic acid was the main metabolite in both species and the 
      beta-glucoronides as well as all-trans-retinoic acid were minor metabolites. 
      However, the plasma AUC values of the administered drug and particularly the 
      4-oxo-metabolite were found to be lower in the monkey as compared to the 
      human.(ABSTRACT TRUNCATED AT 400 WORDS)
FAU - Hummler, H
AU  - Hummler H
AD  - F. Hoffmann-La Roche Ltd., Basel, Switzerland.
FAU - Hendrickx, A G
AU  - Hendrickx AG
FAU - Nau, H
AU  - Nau H
LA  - eng
GR  - RR 00169/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  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Teratogens)
RN  - EH28UP18IF (Isotretinoin)
SB  - IM
MH  - Animals
MH  - Embryo, Mammalian/drug effects
MH  - Female
MH  - Isotretinoin/metabolism/pharmacokinetics/*toxicity
MH  - Macaca fascicularis
MH  - Models, Biological
MH  - Pregnancy
MH  - Teratogens/metabolism/pharmacokinetics/*toxicity
EDAT- 1994/09/01 00:00
MHDA- 1994/09/01 00:01
CRDT- 1994/09/01 00:00
PHST- 1994/09/01 00:00 [pubmed]
PHST- 1994/09/01 00:01 [medline]
PHST- 1994/09/01 00:00 [entrez]
AID - 10.1002/tera.1420500303 [doi]
PST - ppublish
SO  - Teratology. 1994 Sep;50(3):184-93. doi: 10.1002/tera.1420500303.