Investigation of the drug-drug interaction between alpha-lipoic acid and valproate via mitochondrial beta-oxidation.
OBJECTIVE
To investigate the potential drug-drug interaction (DDI) between lipoic acid (LA) and valproate (VA) via the mitochondrial beta-oxidation pathway in rats.


METHODS
In vitro mitochondrial assays were performed to compare the biotransformation of VA to valproyl-CoA (VA-CoA), in the absence and presence of LA. In vitro microsomal and protein binding assays were performed to elucidate their potential DDI at the microsomal metabolism and distribution levels. A pharmacokinetic study was conducted in Lister Hooded rats to ascertain the in vivo DDI between LA and VA.


RESULTS
LA was shown to decrease significantly (p < 0.05) the in vitro formation of VA-CoA in a concentration-dependent manner. Our in vitro assay results confirmed that there was minimal interaction between LA and VA in microsomal metabolism and protein binding. Based on the pharmacokinetic data, the absolute bioavailability of VA was determined to be 1.3 in the presence of LA.


CONCLUSIONS
Our study demonstrated for the first time that there is a potential DDI between LA and VA at the mitochondrial beta-oxidation level. While further clinical study is essential, our preliminary finding suggested that medical practitioners need to be prudent when managing epileptic patients who are co-administered with both VA and LA.
Phua
Lee Cheng
LC
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
New
Lee Sun
LS
Goh
Catherine W
CW
Neo
Aveline H
AH
Browne
Edward R
ER
Chan
Eric C Y
EC
D000818:Animals; D002853:Chromatography, Liquid; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004347:Drug Interactions; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008930:Mitochondria, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D008063:Thioctic Acid / Q000494:pharmacology*; D014635:Valproic Acid / Q000493:pharmacokinetics*
D014635:Valproic Acid; D008063:Thioctic Acid; D002950:Citrate (si)-Synthase