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Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

✍ Scribed by Harri Kanerva; Hannele Huuskonen; Anneli Alhonen-Raatesalmi; Timo Nevalainen; Arto Urtti

Publisher: John Wiley and Sons
Year: 1998
Tongue: English
Weight: 204 KB
Volume: 19
Category: Article
ISSN: 0142-2782
DOI: 10.1002/(sici)1099-081x(1998110)19:8<531::aid-bdd135>3.0.co;2-i

No coin nor oath required. For personal study only.

✦ Synopsis

The pharmacokinetics of a new serotonin 5-HT 2 antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg -1 and intravenous doses of 1, 3 and 6 mg kg -1 were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg -1 doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45 -61%. Deramciclane had a large volume of distribution (32-37 L kg -1 ) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h -1 ) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC 0-increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p= 0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration.

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