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Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing
Author(s) -
Kanerva Harri,
Huuskonen Hannele,
AlhonenRaatesalmi Anneli,
Nevalainen Timo,
Urtti Arto
Publication year - 1998
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(1998110)19:8<531::aid-bdd135>3.0.co;2-i
Subject(s) - pharmacokinetics , pharmacology , bioavailability , beagle , dosing , volume of distribution , oral administration , urine , metabolite , distribution (mathematics) , chemistry , active metabolite , medicine , biochemistry , mathematical analysis , mathematics
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. Copyright © 1998 John Wiley & Sons, Ltd.