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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wójcikowski, J. Syrek, M. Haduch, A. Daniel, W. A. |
| Description | Author Affiliation: Daniel WA ( Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343 Kraków, Poland. nfdaniel@cyf-kr.edu.pl) |
| Abstract | 1. Because of serious side-effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2-week treatment) in rats. 2. Imipramine and amitriptyline (5 and 10 mg kg(-1) i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg(-1) i.p.) and its metabolites (N-desmethylthioridazine, 2-sulphoxide, 2-sulphone, 5-sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed. 3. Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N-demethylation (an increase in K(m)), mono-2-sulphoxidation (an increase in K(m) and a decrease in V(max)) and 5-sulphoxidation (mainly a decrease in V(max)). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism. 4. The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro. 5. Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P-450 towards 5-sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction. 6. The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 2 |
| Volume Number | 131 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2000-09-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Amitriptyline Pharmacology Antidepressive Agents, Tricyclic Imipramine Thioridazine Pharmacokinetics Animals Administration & Dosage Cytochrome P-450 Enzyme System Metabolism Cytochromes B5 Dopamine Antagonists Blood Drug Interactions Microsomes, Liver Drug Effects Rats, Wistar Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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