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

• Published in: Biopharmaceutics & drug disposition 1998-11, Vol.19 (8), p.531-539
• Main Authors: Kanerva, Harri, Huuskonen, Hannele, Alhonen-Raatesalmi, Anneli, Nevalainen, Timo, Urtti, Arto
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Anxiety Agents - administration & dosage; Anti-Anxiety Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Biotransformation; Bornanes - administration & dosage; Bornanes - pharmacokinetics; clearance; Dealkylation; deramciclane fumarate; dog; Dogs; Half-Life; Injections, Intravenous; Medical sciences; Neuropharmacology; non-linear pharmacokinetics; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/(SICI)1099-081X(1998110)19:8<531::AID-BDD135>3.0.CO;2-I

The pharmacokinetics of a new serotonin 5‐HT2 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 AUC0–∞ 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.