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Drug Metabolism and Disposition Fast Forward
First published on August 23, 2005; DOI: 10.1124/dmd.105.003764

0090-9556/05/3311-1708-1716$20.00
DMD 33:1708-1716, 2005

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BIOTRANSFORMATION OF DERAMCICLANE IN PRIMARY HEPATOCYTES OF RAT, MOUSE, RABBIT, DOG, AND HUMAN

Katalin Monostory, Krisztina Kohalmy, Krisztina Ludányi, Gábor Czira, Sándor Holly, László Vereczkey, Iván Ürmös, Imre Klebovich, and László Kóbori

Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary (K.M., K.K., K.L., G.C., S.H., L.V.); EGIS Pharmaceuticals Ltd., Budapest, Hungary (I.Ü., I.K); and Transplantation and Surgery Clinic, Semmelweis University, Budapest, Hungary (L.K.)

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.

Address correspondence to: Katalin Monostory, P.O. Box 17, Budapest, H-1525 Hungary. E-mail address: monostor{at}chemres.hu




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K. Monostory, K. Kohalmy, E. Hazai, L. Vereczkey, and L. Kobori
ROLE OF CYP2E1 IN DERAMCICLANE METABOLISM
Drug Metab. Dispos., November 1, 2005; 33(11): 1717 - 1722.
[Abstract] [Full Text] [PDF]


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