PURPOSE: 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.
PURPOSE: 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 epilepticpatients who are co-administered with both VA and LA.
Authors: Srikanth Sola; Muhammad Q S Mir; Faiz A Cheema; Nadya Khan-Merchant; Rekha G Menon; Sampath Parthasarathy; Bobby V Khan Journal: Circulation Date: 2005-01-17 Impact factor: 29.690
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Authors: M F Silva; J P Ruiter; L IJlst; P Allers; H J ten Brink; C Jakobs; M Duran; I Tavares de Almeida; R J Wanders Journal: Anal Biochem Date: 2001-03-01 Impact factor: 3.365
Authors: K Breithaupt-Grögler; G Niebch; E Schneider; K Erb; R Hermann; H H Blume; B S Schug; G G Belz Journal: Eur J Pharm Sci Date: 1999-04 Impact factor: 4.384
Authors: Kristi L Burns; Leslie T Gelbaum; M Cameron Sullards; David E Bostwick; Sheldon W May Journal: J Biol Chem Date: 2005-02-11 Impact factor: 5.157
Authors: Margarida F B Silva; Lodewijk Ijlst; Paul Allers; Cornelis Jakobs; Marinus Duran; Isabel Tavares de Almeida; Ronald J A Wanders Journal: Drug Metab Dispos Date: 2004-11 Impact factor: 3.922