TY - JOUR T1 - Toxicokinetics and Metabolism of 1,2-Diethylbenzene in Male Sprague Dawley Rats—Part 2: Evidence for in Vitro and in Vivo Stereoselectivity of 1,2-Diethylbenzene Metabolism JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 868 LP - 876 VL - 29 IS - 6 AU - Jean Paul Payan AU - Benoit Cossec AU - Dominique Beydon AU - Jean Paul Fabry AU - Elisabeth Ferrari Y1 - 2001/06/01 UR - http://dmd.aspetjournals.org/content/29/6/868.abstract N2 - In a previous study, it was shown that the neurotoxic compound 1,2-diethylbenzene (1,2-DEB) is mainly hydroxylated in the alkyl chain to give 1-(2′-ethylphenyl)ethanol (1,2-EPE) and excreted in urine of rats as two glucuronide compounds (GA1 and GA2). Some findings have suggested that the two enantiomers of 1,2-EPE are formed in vivo. In the present study, a chiral high-performance liquid chromatography method was developed to separate the two enantiomers of 1,2-EPE from a synthesized racemic mixture. Absolute configuration of both enantiomers was determined after esterification with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid and analysis of their 1H NMR spectra in CCl4 added with Eu (fod)3. The two main urinary metabolites, GA1 and GA2, from [14C]1,2-DEB-treated Sprague-Dawley rats (80 mg/kg, i.p.) were identified, after hydrolysis with β-glucuronidase from Escherichia coli, as (R) and (S) glucuronide conjugates of 1,2-EPE, respectively. In vitro hydroxylation of 1,2-DEB and glucuroconjugation of 1,2-EPE were under stereoselective control in S9 fraction or microsomes from male Sprague-Dawley rat liver. TheV max and K mconstants for (R)1,2-EPE enantiomer formation determined in S9 fraction were greater than those for the (S) enantiomer. In the plasma of bile duct-cannulated rats, the ratio was 1.2 ± 0.02 over the 1- to 4-h period after oral administration of [14C]1,2-DEB (100 mg/kg). In contrast, the glucuroconjugation rate of (S)1,2-DEB enantiomer was 4 times that of (R)1,2-EPE glucuroconjugation. A similar ratio of (R) to (S)1,2-EPE glucuronide conjugates was obtained in the plasma of bile duct-cannulated rats. The American Society for Pharmacology and Experimental Therapeutics ER -