Summary
Alaproclate, a selective serotonin reuptake inhibitor, presently undergoing clinical trial for the treatment of major depressive disorders, has been shown to inhibit hexobarbital metabolism in mice. In the present study the influence of oral alaproclate on the total plasma clearance of antipyrine and on the formation of its metabolites was investigated in 10 healthy volunteers. The peak level of alaproclate was reached after about 1.5 h, and after a distribution phase, its plasma elimination half-life was between 3.0 and 3.5 h. Antipyrine tests were performed before treatment, during the first four doses and after the seventh dose of alaproclate 200 mg/day. During treatment, total plasma antipyrine clearance and the clearance for production of all antipyrine metabolites were reduced by 30%, indicating non-selective inhibition of oxidative drug-metabolizing enzyme activity in man by alaproclate. After the last dose of alaproclate, antipyrine plasma clearance and the clearance to its metabolites returned to control values. In order to allow more detailed evaluation of the results, the time course of the clearances for production of metabolites was investigated. This revealed that the extent of inhibition of metabolite formation by alaproclate was dependent on the plasma alaproclate level, indicating a rapidly reversible inhibition.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arthur GE, Boyes RN, Brown D, Lundström J, Lindgren JE, McLure J, Scott DB (1980) Pharmacokinetics of alaproclate, a specific 5-HT uptake inhibitor. In: Turner P, Padgham C (eds). Abstracts World Conference on Clinical Pharmacology and Therapeutics, London, August 3–9, no. 0574. Macmillan Publishers
Benet LZ, Galeazzi RL (1979) Non-compartmental determination of the steady-state volume of distribution. J Pharm Sci 68: 1071–1074
Breimer DD (1983) Interindividual variations in drug disposition. Clinical implications and methods of investigation. Clin Pharmacokinet 8: 371–377
Breimer DD, Vermeulen NPE, Danhof M, Teunissen MWE, Joeres RP, Van der Graaff M (1984) Assessment and prediction of in vivo oxidative drug metabolizing activity. In: Benet LZ, Levy G (eds) Pharmacokinetics. A modern view. Plenum Press, New York (in press)
Cott JM, Ögren SO (1980) Antidepressant drugs and ethanol: behavioral and pharmacokinetic interactions in mice. J Neural Transm 48: 223–240
Danhof M, Krom DB, Breimer DD (1979a) Studies on the different metabolic pathways of antipyrine in rats. Influence of phenobarbital and 3-methylcholanthrene treatment. Xenobiotica 9: 695–702
Danhof M, De Groot-Van der Vis E, Breimer DD (1979b) Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high performance liquid chromatography and some preliminary results in man. Pharmacology 18: 210–233
Danhof M, Teunissen MWE, Breimer DD (1982a) 3-Hydroxymethylantipyrine excretion in urine after an oral dose of antipyrine. A reconsideration of previously published data and synthesis of a pure reference substance. Pharmacology 24: 181–184
Danhof M, Van Zuilen A, Boeijinga JK, Breimer DD (1982b) Studies of the different metabolic pathways of antipyrine in man. Oral versus i. v. administration and the influence of urinary collection time. Eur J Clin Pharmacol 21: 433–441
Greenblatt DJ, Franke K, Huffman DH (1978) Impairment of antipyrine clearance in humans by propranolol. Circulation 57: 1161–1164
Koike E, Iida H, Okauna M, Kashioka A (1954) Organic pigments. II. Synthesis of 1-phenyl-3-methyl-5-pyrazolon and its derivatives. J Chem Soc Japan 57: 56–58
Lindberg UH, Thorberg SO, Bengtsson S, Renyi AL, Ross SB, Ögren SO (1978) Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by α-amino acid esters of phenethyl alcohols. J Med Chem 21: 448–456
O'Malley K, Browning M, Stevenson IH, Turnbull MJ (1973) Stimulation of drug metabolism in man by tricyclic antidepressants. Eur J Clin Pharmacol 6: 102–106
O'Malley K, Stevenson IH, Crooks J (1972) Impairment of human drug metabolism by oral contraceptive steroids. Clin Pharmacol Ther 13: 552–557
Pschorr R (1897) Über das 1-phenyl-2,3-dimethyl-4-oxy-5-pyrazolon (4-oxy-antipyrin). Liebigs Annln Chem 293: 49–55
Serlin MJ, Mossmann S, Sibeon RG, Breckenridge AM, Williams JRB, Attwood JL, Willoughby JMT (1979) Cimetidine: interaction with oral anticoagulants in man. Lancet 2: 317–319
Teunissen MWE, Joeres RP, Vermeulen NPE, Breimer DD (1983a) Influence of 9-hydroxyellipticine and 3-methylcholan-threne treatment on antipyrine metabolite formation in rats in vivo. Xenobiotica 13: 223–231
Teunissen MWE, Meerburg-Van der Torren JE, Vermeulen NPE, Breimer DD (1983b) Automated HPLC-determination of antipyrine and its main metabolites in plasma, saliva and urine, including, 4,4′-dihydroxyantipyrine. J Chromatogr 278: 367–378
Teunissen MWE, Srivastava AK, Breimer DD (1982) Influence of sex and oral contraceptive steroids on antipyrine metabolite formation. Clin Pharmacol Ther 32: 240–246
Vesell ES, Passananti GT, Aurori KC (1975) Anomalous results of studies on drug interaction in man. I. Nortriptyline and antipyrine. Pharmacology 13: 101–111
Vesell ES, Passananti GT, Hepner GW (1976) Interaction between antipyrine and aminopyrine. Clin Pharmacol Ther 20: 661–669
Vesell ES (1977) Genetic and environmental factors affecting drug disposition in man. Clin Pharmacol Ther 22: 659–679
Yoshimura H, Shimeno H, Tsukamoto H (1971) Metabolism of drugs. LIX. A new metabolite of antipyrine. Biochem Pharmacol 17: 1511–1516
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Teunissen, M.W.E., Wahlén, A., Vinnars, E. et al. Influence of alaproclate on antipyrine metabolite formation in man. Eur J Clin Pharmacol 27, 447–452 (1984). https://doi.org/10.1007/BF00549593
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00549593