No enantiomeric interconversion occurred during the procedure of this assay. This method had a precision better than 15% for all analytes and a LOQ of 0.1 mg/L (serum) and 0.2 mg/L (urine) for each MHD enantiomer, and 0.4 mg/L (urine) for each of the DHD enantiomers. published an enantioselective HPLC method for monitoring the enantiomers of MHD and its metabolite carbamazepine-10,11- trans-dihydrodiol (DHD Figure 45.1) (18). were the first to describe a stereoselective (enantioselective) method for the simultaneous determination of the two enantiomers, ( S)-MHD and ( R)-MHD, with an LOQ of 0.1 mg/L (17). described a nonstereoselective gas chromatographic assay for OXC and its metabolites (16). The first methods were nonstereoselective high-performance liquid chromatography (HPLC) methods with a limit of quantification (LOQ) of 2 µmol/L or 0.5 mg/L (14,15). Consequently, the published methods of determination for OXC actually measure plasma levels of MHD and in some cases OXC as well. OXC is a prodrug of MHD, which is the principal active entity of OXC. The starting material, 10-methoxycarbazepine, is produced by reacting 10-methoxy-5H-dibenzazepine with phosgene in toluene to give the 10-methoxy-5H-dibenzoazepine-5-carbonyl chloride, which is then converted in ethanol with ammonia to the amide (13). The compound is prepared by hydrolysis of 10-methoxycarbazepine in dilute hydrochloric or sulfuric acid (13). OXC is a neutral lipophilic compound (molecular weight 252.3) with a melting point of 215☌ to 216☌ and low water solubility. In a study conducted in rats, no marked difference in anticonvulsant activity was found between CBZ, OXC, and racemic MHD (11,12). Therefore, in humans MHD is in essence the active entity of OXC. However, OXC is not only a soft drug analog of CBZ but a prodrug of MHD because in humans it undergoes an extensive presystemic first-pass conversion to MHD. Thus, OXC can be regarded a soft drug analog of CBZ owing to its lack of oxidative metabolism (10). Whereas CBZ metabolism to CBZ-E is mediated by cytochrome P450 (CYP) isoforms CYP3A4 and CYP2C8 (6) and is highly susceptible to induction and drug interactions, the biotransformation of OXC to MHD is catalyzed by reductases that are much less subject to enzyme induction (7, 8, 9). Whereas CBZ undergoes oxidative metabolism to carbamazepine-10,11-epoxide (CBZ-E), OXC is rapidly and extensively reduced by cytosolic enzymes in the liver to its monohydroxylated derivative (MHD) (2) (Figure 45.1). The main advantage of OXC is its nonoxidative metabolic pathway, which implies lower induction potential and fewer drug interactions (3, 4, 5). OXC was developed as a “second-generation” and follow-up compound to CBZ (1,2). OXC is a new antiepileptic drug (AED) that has been approved worldwide for the treatment of different kinds of partial-onset seizures and generalized tonic-clonic seizures (1, 2, 3, 4, 5). Oxcarbazepine (OXC), 10,11-dihydro-10-oxo-carbamazepine or 10-oxo-carbazepine (Figure 45.1) is a 10-keto analog of carbamazepine (CBZ). Eisenberg Professor of Pharmacy, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel Antiepileptic Drugs, 5th Edition Oxcarbazepine 45 Chemistry, Biotransformation, and Pharmacokineticsĭavid H.
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