{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T13:46:33Z","timestamp":1776001593270,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2000,12,1]],"date-time":"2000-12-01T00:00:00Z","timestamp":975628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The aim of this study was to search for possible effects of imipramine and amitriptyline on the pharmacokinetics and metabolism of perazine at steady state in rats. Perazine (10 mg kg\u22121, i.p.) was administered to rats twice daily for two weeks, alone or jointly with imipramine or amitriptyline (10 mg kg\u22121 i.p.). Concentrations of perazine and its two main metabolites (5-sulphoxide and N-desmethylperazine) in the plasma and brain were measured at 30 min (Cmax), 6h and 12h (slow disposition phase) after the last dose of the drugs. Liver microsomes were prepared 24 h after withdrawal of the drugs.<\/jats:p>\n               <jats:p>Amitriptyline increased the plasma and brain concentrations of perazine (up to 300% of the control) and N-desmethylperazine, while not affecting those of 5-sulphoxide. Imipramine only tended to increase the neuroleptic concentration in the plasma and brain. Studies with control liver microsomes showed that amitriptyline and imipramine added to the incubation mixture in-vitro, competitively inhibited N-demethylation (Ki (inhibition constant) = 16 \u03bcM and 164 \u03bcM, respectively) and 5-sulphoxidation (Ki = 57 \u03bcM and 86 \u03bcM, respectively) of perazine, amitriptyline being a more potent inhibitor of perazine metabolism, especially with respect to N-demethylation. Studies with microsomes of rats treated chronically with perazine or tricyclic antidepressants, or both, did not show significant differences in the rate of perazine metabolism between perazine- and perazine+antidepressant-treated rats. The data obtained were compared with the results of analogous experiments with promazine and thioridazine.<\/jats:p>\n               <jats:p>It was concluded that elevations of perazine concentration were caused by direct inhibition of the neuroleptic metabolism by the antidepressants. Similar interactions, possibly leading to exacerbation of the pharmacological action of perazine, may be expected in man. Since the interactions between phenothiazines and tricyclic antidepressants may proceed in two directions, reduced doses of both the neuroleptic and the antidepressant are recommended when the drugs are administered jointly.<\/jats:p>","DOI":"10.1211\/0022357001777685","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T22:04:05Z","timestamp":1033509845000},"page":"1473-1481","source":"Crossref","is-referenced-by-count":12,"title":["Different Effects of Amitriptyline and Imipramine on the Pharmacokinetics and Metabolism of Perazine in Rats"],"prefix":"10.1093","volume":"52","author":[{"given":"Wladyslawa A","family":"Daniel","sequence":"first","affiliation":[{"name":"Polish Academy of Sciences, Institute of Pharmacology , Sm\u011btna 12, 31\u2013343 Krak\u00f3w,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Syrek","sequence":"additional","affiliation":[{"name":"Polish Academy of Sciences, Institute of Pharmacology , Sm\u011btna 12, 31\u2013343 Krak\u00f3w,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Haduch","sequence":"additional","affiliation":[{"name":"Polish Academy of Sciences, Institute of Pharmacology , Sm\u011btna 12, 31\u2013343 Krak\u00f3w,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacek","family":"W\u00f3jcikowski","sequence":"additional","affiliation":[{"name":"Polish Academy of Sciences, Institute of Pharmacology , Sm\u011btna 12, 31\u2013343 Krak\u00f3w,","place":["Poland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2000,12,1]]},"reference":[{"key":"2024103110052594700_cit1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1001\/archpsyc.1988.01800250095013","article-title":"Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses","volume":"45","author":"Baldessarini","year":"1988","journal-title":"Arch. 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Pharmacol."},{"key":"2024103110052594700_cit8","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/clpt.1991.77","article-title":"Role of P4502D6, the targed of the sparteine-debrisoquine oxidation polymorphism, in the metabolism of imipramine","volume":"49","author":"Br\u00f8sen","year":"1991","journal-title":"Clin. Pharmacol. Ther."},{"key":"2024103110052594700_cit9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0306-3623(95)02008-X","article-title":"Plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after one and six half-life repeated administrations to rats","volume":"27","author":"Coudore","year":"1996","journal-title":"Gen. Pharmacol."},{"key":"2024103110052594700_cit10","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/clpt.1989.109","article-title":"Disposition of perphenazine is related to the polymorphic hydroxylation in human beings","volume":"46","author":"Dahl-Puustinen","year":"1989","journal-title":"Clin. Pharmacol. Ther."},{"key":"2024103110052594700_cit11","first-page":"197","article-title":"Pharmacokinetic interaction between imipramine and antidepressant neuroleptics in rats","volume":"43","author":"Daniel","year":"1991","journal-title":"Pol. J. Pharmacol. Pharm."},{"key":"2024103110052594700_cit12","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1016\/0006-2952(86)90420-X","article-title":"The effect of neuroleptics on imipramine demethylation in rat liver microsomes and imipramine and desipramine level in the rat brain","volume":"35","author":"Daniel","year":"1986","journal-title":"Biochem. 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Toxicol."},{"key":"2024103110052594700_cit19","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1176\/ajp.131.8.863","article-title":"Influence of neuroleptics and benzodiazepines on metabolism of tricyclic antidepressants in man","volume":"131","author":"Gram","year":"1974","journal-title":"Am. J. Psychiat."},{"key":"2024103110052594700_cit20","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1159\/000117644","article-title":"Pharmacokinetic interaction between amitriptyline and neuroleptics","volume":"4","author":"Jus","year":"1978","journal-title":"Neuropsychobiology"},{"key":"2024103110052594700_cit21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/BF00404219","article-title":"Urinary metabolites of 10-[3\u2032-(4-methylpiperazinyl)-propyl]-phenothiazine (perazine) in psychiatric patients - II. 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Pharmacol."},{"key":"2024103110052594700_cit36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/clpt.1988.76","article-title":"Inhibition of desipramine 2-hydroxylation by quinidine and quinine","volume":"43","author":"Steiner","year":"1988","journal-title":"Clin. Pharmacol. Ther."},{"key":"2024103110052594700_cit37","first-page":"453","article-title":"Promazine Pharmacokinetics during concurrent treatment with tricyclic antidepressants","volume":"49","author":"Syrek","year":"1997","journal-title":"Pol. J. 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