RT Journal Article
SR Electronic
T1 S-2-PENTYL-4-PENTYNOIC HYDROXAMIC ACID AND ITS METABOLITE S-2-PENTYL-4-PENTYNOIC ACID IN THE NMRI-EXENCEPHALY-MOUSE MODEL: PHARMACOKINETIC PROFILES, TERATOGENIC EFFECTS, AND HISTONE DEACETYLASE INHIBITION ABILITIES OF FURTHER VALPROIC ACID HYDROXAMATES AND AMIDES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 612
OP 620
DO 10.1124/dmd.105.008078
VO 34
IS 4
A1 Daniel Eikel
A1 Katrin Hoffmann
A1 Karolin Zoll
A1 Alfonso Lampen
A1 Heinz Nau
YR 2006
UL http://dmd.aspetjournals.org/content/34/4/612.abstract
AB Structure-activity relationship studies of valproic acid (VPA) derivatives have revealed a quantitative correlation between histone deacetylase (HDAC) inhibition and induction of neural tube defects (NTDs) in the NMRI-exencephaly-mouse model, but this correlation has been, so far, limited to congeners with a carboxylic acid function. Whereas the classical HDAC inhibitor trichostatin A is active only as a hydroxamate but not as a carboxylic acid, we found that neither VPA amides nor hydroxamates inhibit HDACs, but can cause NTDs; e.g., 2-pentyl-4-pentynoic hydroxamic acid with its S-enantiomer being the potent teratogen. We therefore investigated the hypothesis that hydroxamic acid derivatives of VPA might be metabolized in vivo and may possibly be pro-teratogenic, as had been shown for valpromide but not valproic hydroxamic acid. We developed two stereoselective quantification methods based on chiral derivatization of VPA hydroxamates with (1R,2S,5R)-(–)-menthylchloroformate and carboxylic acid derivatives with (S)-(–)-1-naphthylethylamine, followed by gas chromatography-nitrogen phosphor detector analysis of biological samples. We then determined the pharmacokinetic profiles of S-2-pentyl-4-pentynoic hydroxamic acid and of S-2-pentyl-4-pentynoic acid in mice. S-2-Pentyl-4-pentynoic hydroxamic acid was found to be extensively metabolized to the corresponding carboxylic acid without affecting the stereochemistry at position C2. Furthermore, the metabolite S-2-pentyl-4-pentynoic acid was found to be very stable in vivo, with an extended half-life of 4.2 h compared with that of VPA, 1.4 h. Comparison of the individual HDAC inhibition abilities of additional VPA amides and hydroxamates, as measured by cellular and enzymatic assays, led us to the conclusion that both classes of VPA derivatives can be pro-teratogenic. The American Society for Pharmacology and Experimental Therapeutics