Pharmacokinetics of phenothiazine neuroleptics after chronic coadministration of carbamazepine.
The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced. In conclusion, carbamazepine given jointly with thioridazine or promazine at pharmacological doses to rats accelerates the metabolism of the neuroleptics, which is not the case with perazine. The observed induction proceeds by metabolic pathways other than N-demethylation or sulfoxidation. The different effect of carbamazepine on the N-demethylation of thioridazine and perazine in liver microsomes of control and carbamazepine-treated rats implicates that the two reactions are not catalyzed by the same enzyme. Such an induction of neuroleptic metabolism by carbamazepine in patients may worsen psychotic symptoms.
Daniel
W A
WA
Department of Pharmacokinetics and Drug Metabolism, Polish Academy of Sciences, Kraków, Poland.
Syrek
M
M
Haduch
A
A
Wójcikowski
J
J
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004049:Diethylcarbamazine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010464:Perazine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013881:Thioridazine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors
D014150:Antipsychotic Agents; D016859:Lipoxygenase Inhibitors; D010464:Perazine; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D013881:Thioridazine; D004049:Diethylcarbamazine