VALNOCTAMIDE, VALPROMIDE AND VALNOCTIC ACID ARE MUCH LESS TERATOGENICIN MICE THAN VALPROIC ACID

The teratogenic properties of valproic acid (VPA) and its analogues de pend to a great extent on their chemical structure, We investigated th e structure-teratogenicity relationships of VPA, its structural isomer , valnoctic acid (VCA), and their two amide analogues, valpromide (VPD ) and valnoctamide (VCD), respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning of day 8 of gestation. Embryolet hality, fetal weight and exencephaly rates were recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA and VCD pro duced only 1% exencephaly (control values between 0 and 1%). VPA-treat ed mice also had increased embryolethality rates (52%). There was no s ignificant change of embryolethality in the other treatment groups. Ph armacokinetic studies showed that VCD was eliminated from plasma at a slower rate than VPA. Also, the residual teratogenic activity of VPD w as not accounted for by the relatively small amounts of its hydrolysis product VPA. This study indicates that VPD, VCA and VCD were distinct ly less teratogenic than VPA. Apparently the amidation of the free car boxylic group and/or methyl-substitution at the beta-position of the c arbon chain greatly decreased the teratogenic activity of VPA. (C) 199 8 Elsevier Science B.V. All rights reserved.