Interaction of carbamazepine and promethazine in rabbits

Abstract

The interaction of carbamazepine and promethazine in rabbits has been investigated. The influence of this interaction on the processes of biotransformation in the liver was revealed. The drugs were administered as single oral doses (100 mg of each drug) as well as simultaneously with an interval of 15 min. The sequence of administration of the drugs was varied. The influence of promethazine on the pharmacokinetics of carbamazepine is expressed by: (a) strong suppression of carbamazepine's level in plasma and appearance of multiple peaks of carbamazepine; (b) suppression of biotransformation of carbamazepine into carbamazepine-10,11-epoxide at the initial stages and its increase in the intermediate stages. These data are explained by the active capture of carbamazepine by liver at its primary transferal through the liver and sufficient presystem elimination of carbamazepine in the presence of promethazine. The character of kinetic curves of promethazine varies substantially under the influence of carbamazepine. However, this change is not as strong as in case of carbamazepine. The concentration of promethazine in plasma varies slightly and multiple peaks are not observed. The rate of terminal elimination of promethazine varies and abrupt prolonged segments of elimination appear at the initial and terminal stages of the process in return. These data perhaps indicate the induction of biotransformation of promethazine in the presence of carbamazepine-an inductor of microsomal liver enzymes. The changes of kinetics of promethazine and carbamazepine by simultaneous administration as compared with their administration separately, as well as a comparative consideration of pharmacokinetics of promethazine and carbamazepine by simultaneous administration show the existence of competition in the elimination between these drugs and the periodic saturation of liver for their biotransformation.

Interaction of surface‐active drugs in rabbits

“…The modifying influence of PMZ is more strongly revealed in the case of (PMZ + CPM), where PMZ enters the organism first. The analogous effect was observed by us on the study of the interaction of PMZ and carbamazepine, which does not possess a first-pass effect (Rukhadze et al, 2003). We previously arrived at the conclusion that PMZ prepares the liver in some way for the capture of carbamazepine on its first pass through the liver; as a result the sharp suppression of carbamazepine content in blood plasma occurs on simultaneous administration of carbamazepine and PMZ.…”

“…they represent the constituents of lytic cocktail, which is in widespread in pediatric patients (Mashkowsky, 2000;American Academy of Pediatrics, 1995;Santhanakrishnan, 2000). The interactions of CPM and PMZ with the antiepileptic drug carbamazepine were previously studied (Rukhadze et al, 1999(Rukhadze et al, , 2003. Carbamazepine induces microsomal liver enzymes (Levy and Pitlick, 1982;Eadie and Tyrer, 1983;Kholodov and Yakovlev, 1985).…”

“…Carbamazepine increases biotransformation of both CPM and PMZ. The surfactants CPM and PMZ, in their turn, suppress the biotransformation of carbamazepine (Rukhadze et al, 1999(Rukhadze et al, , 2003. Theories on (a) the saturation of liver enzymes for biotransformation, (b) competition for elimination between drugs, (c) induction of microsomal enzymes of liver with carbamazepine, (d) the preparation of different tissues of organism for the capture of carbamazepine under the influence of surfactants (tissues of the gastro-intestinal tract in the case of CPM, but tissues of the liver in the case of PMZ) and (e) formation of both micelles and mixed micelles in the gastro-intestinal tract have been proposed for the explanation of these results (Rukhadze et al, 1999(Rukhadze et al, , 2003.…”

Drug–Drug Interactions With Over-The-Counter Medicines: Mind the Unprescribed

“…A previous animal study of promethazine in rabbits indicated that the drug is an inducer of microsomal enzymes and is itself a victim of CYP induction caused by carbamazepine. 18 Similarly, doxylamine was found to induce hepatic metabolism in mice 19 ; however, to date, there is no published interaction study in humans. On the other hand, CYP2D6 inhibition by diphenhydramine is well documented in the literature [20][21][22] (Table 2).…”

Studies on the interaction between promethazine and human serum albumin in the presence of flavonoids by spectroscopic and molecular modeling techniques

“…For example, patients taking PMT with ketorolac can cause delirium [15]. The character of kinetic curves of promethazine changed substantially and the elimination of PMT in the blood was prolonged under the influence of carbamazepine and chlorpromazine [16,17]. In addition, patients should be warned not consume anything (drugs and foods) containing caffeine at the treatment by PMT, as caffeine will cause increasing of maximum and current concentration of PMT and its prolongation in organism [18], which indicates that the food-drug interaction should be considered in the period of the drugs treatment.…”