Influence of repeated administration of cimetidine on the pharmacokinetics and pharmacodynamics of adinazolam in healthy subjects
- 18 Downloads
Adinazolam is a new triazolobenzodiazepine bearing an alkyl-amino side chain. A cross-over double-blind placebo controlled study was carried out in 12 healthy volunteers, in order to check the possible interaction between cimetidine and adinazolam after repeated co-administration.
Cimetidine or placebo were given during 17 days. Beginning on Day 8 of each treatment, adinazolam was given in the increasing doses following sequence of doses for 3 days: 10 mg b.i.d., 20 mg b.i.d. and 20 mg t.i.d. A pharmacokinetic and pharmacodynamic study was performed on the third day at each dose. A wash-out of three weeks was included between the two treatments.
Cimetidine increased significantly the AUC values of both adinazolam and N-desmethyladinazolam, reduced the oral clearance of adinazolam, and prolonged adinazolam's half-life.
The digit symbol substitution test was significantly affected at each dose level while the manual dexterity was marginally impaired by adinazolam plus cimetidine.
Saftee-up interview and Clyde mood scale indicated an increased sedation under adinazolam plus cimetidine in four subjects.
Key wordsadinazolam cimetidine pharmacokinetics pharmacodynamics healthy volunteers adverse effects
Unable to display preview. Download preview PDF.
- 1.Lahti RA, Sethy VH, Barsuhn C, Hester JB (1983) Pharmacological profile of the antidepressant adinazolam, a triazolobenzodiazepine. Neuropharmacology 22: 1277–1282Google Scholar
- 2.Turmel A, De Montigny C (1984) Sensitization of rat forebrain neurons to serotonin by adinazolam, an antidepressant triazolobenzodiazepine. Eur J Pharmacol 99: 241–244Google Scholar
- 3.Sethy VA, Collins RJ, Daniels DG (1984) Determination of biological activity of adinazolam and its metabolites. J Pharm Pharmacol 36: 546–548Google Scholar
- 4.Pyke RE, Cohn JB, Feighner JP, Smith WT (1983) Open-label studies of adinazolam in severe depression. Psychopharmacology Bull 19: 96–98Google Scholar
- 5.Smith WT, Glaudin V (1986) Double-blind efficacy and safety study comparing adinazolam mesylate and placebo in depressed inpatients. Acta Psychiatr Scand 74: 238–245Google Scholar
- 6.Amsterdam JD, Kaplan M, Potter L, Bloom L, Rickels K (1986) Adinazolam, a new triazolobenzodiazepine, and imipramine in the treatment of major depressive disorder. Psychopharmacology 88: 484–488Google Scholar
- 7.Somogyi A, Muirhead M (1987) Pharmacokinetic interactions of cimetidine 1987. Clin Pharmacokinet 12: 321–366Google Scholar
- 8.Descotes J, Simonet R, Loupi E, Evreux JC (1986) Interactions medicamenteuses par inhibition enzymatique. Therapie 41: 349–351Google Scholar
- 9.Pourbaix S, Desager JP, Hulhoven R, Smith RB, Harvengt C (1985) Pharmacokinetic consequences of long-term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects. Int J Clin Pharmacol Ther Toxicol 23: 447–451Google Scholar
- 10.Levine J (1985) Safety rating system, US Health Department (as modified by Upjohn, Kalamazoo, USA)Google Scholar
- 11.Clyde DJ (1963) Manual for the Clyde Mood scale. Clyde Computing Service, MiamiGoogle Scholar
- 12.Wechsler (1955) A manual for the Wechsler adult intelligence scale. Psychological Corporation, New YorkGoogle Scholar
- 13.Jensen AR, Thower WD (1966) The Stroop color-word test: A review. Acta Psychologica 25: 36–93Google Scholar
- 14.Peng GW (1984) Assay of adinazolam in plasma by liquid chromatography. J Pharm Sci 73: 1173–1175Google Scholar
- 15.Desager JP (1986) Applicability of disposable extraction columns to CNS-drug analysis. In: Reid E, Scales B, Wilson ID (eds) Bioactive analytes, including CNS drugs, peptides and enantiomers. Plenum, New YorkGoogle Scholar
- 16.Mihaly GW, Cockbain S, Jones DB, Hanson RG, Smallwood RA (1982) High-pressure liquid chromatographic determination of cimetidine in plasma and urine. J Pharm Sci 71: 590–592Google Scholar
- 17.SAS User Guide, Basics and statistics, version 5, SAS Institute Inc., Box 8000, Cary, NCGoogle Scholar
- 18.Sethy VH, Francis JW, Day JS (1986) The effect of proadifen on the metabolism of adinazolam. J Pharm Pharmacol 38: 631–632Google Scholar