TY - JOUR T1 - BIOTRANSFORMATION OF DERAMCICLANE IN PRIMARY HEPATOCYTES OF RAT, MOUSE, RABBIT, DOG, AND HUMAN JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1708 LP - 1716 DO - 10.1124/dmd.105.003764 VL - 33 IS - 11 AU - Katalin Monostory AU - Krisztina Kőhalmy AU - Krisztina Ludányi AU - Gábor Czira AU - Sándor Holly AU - László Vereczkey AU - Iván Ürmös AU - Imre Klebovich AU - László Kóbori Y1 - 2005/11/01 UR - http://dmd.aspetjournals.org/content/33/11/1708.abstract N2 - The metabolic fate of deramciclane [(1R,2S,4R)-(–)-2-phenyl-2-(2′-dimethylamino-ethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane], a new anxiolytic drug candidate, has been determined in rat, mouse, rabbit, dog, and human hepatocytes. Rat and rabbit cells were the most active, whereas the rate of metabolism was quite slow in human hepatocytes. During biotransformation, deramciclane underwent side chain modification and oxidation at several positions of the molecule. The side chain modification led to the formation of N-desmethyl deramciclane and phenylborneol. The oxidation of deramciclane resulted in several hydroxy-, carboxy-, and N-oxide derivatives. The hydroxylation took place at primary or secondary carbons of the camphor ring as well as at the side chain; furthermore, dihydroxylated derivatives were also found. The side chain-modified metabolites were also oxidized to hydroxy- or carboxy-derivatives. Conjugation of phase I metabolites, as a route of elimination, was also observed in rat, rabbit, and dog hepatocytes. Although there were some species differences in biotransformation of deramciclane, it was concluded that phase I metabolism in human liver cells seemed to be similar to the metabolism in the hepatocytes isolated from rat. With careful approach, the rat model may be considered to be predictive for human metabolism of deramciclane. The American Society for Pharmacology and Experimental Therapeutics ER -