PMID- 3149039
OWN - NLM
STAT- MEDLINE
DCOM- 19890501
LR  - 20131121
IS  - 0040-3709 (Print)
IS  - 0040-3709 (Linking)
VI  - 38
IP  - 4
DP  - 1988 Oct
TI  - Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: 
      an interspecies comparison.
PG  - 329-45
AB  - This study was undertaken to assess the developmental toxicity and drug 
      distributional and metabolic characteristics of prenatal valproic acid (VPA) 
      exposure in rhesus monkeys. Oral administration of 20-600 mg/kg/day VPA 
      (approximately 1-15 X human therapeutic dose) to 33 animals on variable 
      gestational days (GD) during organogenesis resulted in dose-dependent 
      developmental toxicity manifested as increased embryo/fetal mortality, 
      intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic 
      plasma elimination curves were observed for total and free VPA on the first (GD 
      21) and last (GD 50) days of treatment in the 100- and 200-mg/kg/day dose groups. 
      VPA exhibited dose-independent elimination kinetics at the plasma concentrations 
      observed in this study. There was no significant change in pharmacokinetic 
      parameters (maternal plasma elimination rate, area under the curve, peak plasma 
      concentration) between the first and last days of treatment at either dose level. 
      Placental transfer studies indicated that embryos were exposed to half the free 
      VPA concentrations present in maternal plasma on GD 37. Comparisons of 
      interspecies sensitivity to VPA-induced developmental toxicity in the mouse, rat, 
      monkey, and man are made.
FAU - Hendrickx, A G
AU  - Hendrickx AG
AD  - California Primate Research Center, University of California, Davis 95616.
FAU - Nau, H
AU  - Nau H
FAU - Binkerd, P
AU  - Binkerd P
FAU - Rowland, J M
AU  - Rowland JM
FAU - Rowland, J R
AU  - Rowland JR
FAU - Cukierski, M J
AU  - Cukierski MJ
FAU - Cukierski, M A
AU  - Cukierski MA
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  - United States
TA  - Teratology
JT  - Teratology
JID - 0153257
RN  - 0 (Blood Proteins)
RN  - 0 (Teratogens)
RN  - 614OI1Z5WI (Valproic Acid)
SB  - IM
MH  - *Abnormalities, Drug-Induced
MH  - Animals
MH  - Blood Proteins/metabolism
MH  - Female
MH  - Fetus/*drug effects
MH  - Macaca/*metabolism
MH  - Macaca mulatta/*metabolism
MH  - Protein Binding
MH  - Species Specificity
MH  - *Teratogens
MH  - Valproic Acid/blood/pharmacokinetics/*toxicity
EDAT- 1988/10/01 00:00
MHDA- 1988/10/01 00:01
CRDT- 1988/10/01 00:00
PHST- 1988/10/01 00:00 [pubmed]
PHST- 1988/10/01 00:01 [medline]
PHST- 1988/10/01 00:00 [entrez]
AID - 10.1002/tera.1420380405 [doi]
PST - ppublish
SO  - Teratology. 1988 Oct;38(4):329-45. doi: 10.1002/tera.1420380405.