Effect of carbamazepine on the pharmacokinetics of promazine.
Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of mania, manic-depressive illness and schizophrenia. The present study was aimed at assessing the influence of carbamazepine on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or carbamazepine twice daily for two weeks (promazine, 10 mg/kg ip; carbamazepine, 15 mg/kg ip during the 1st, and 20 mg/kg ip during the 2nd week of treatment). In a short time (1 h) after administration, carbamazepine had a tendency to increase the concentration of promazine in the blood plasma and brain. Lineweaver-Burk's analysis showed that carbamazepine added in vitro competitively inhibited the N-demethylation of promazine in liver microsomes, without affecting the sulphoxidation process. The effect was reflected in vivo (1 h) by an increased promazine/desmethylpromazine ratio. After a long time interval (6 h, 12 h), carbamazepine decreased the concentration of promazine and its metabolites. In vitro studies into the promazine metabolism, conducted on microsomes from rats treated with promazine and/or carbamazepine, did not show acceleration of its demethylation or sulphoxidation by carbamazepine. The obtained results suggest that induction of promazine metabolism by carbamazepine involves metabolic pathways other than N-demethylation or sulphoxidation. It has been concluded that when a phenothiazine neuroleptic, such as promazine, is administered jointly with carbamazepine, a slight increase in the neuroleptic concentration may be expected in a short time after administration, followed by its significant decrease.
Syrek
M
M
Department of Pharmacokinetics and Drug Metabolism, Polish Academy of Sciences, Kraków, Poland.
Wójcikowski
J
J
Daniel
W
W
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D004347:Drug Interactions; D004357:Drug Synergism; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011395:Promazine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D014150:Antipsychotic Agents; D002220:Carbamazepine; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D011395:Promazine