UBC Theses and Dissertations
Studies of carbamazepine metabolism Webster, Donald Shaw
The objective of this study was to examine aspects of carbamazepine metabolism, in order to contribute to a long term goal of a thorough examination of how the metabolism of carbamazepine is influenced by other drugs. The first set of experiments were designed with the intent of determining values for the pharmacokinetic parameters of carbamazepine metabolism in male New Zealand white rabbits. Values were obtained for t[sub max] (60-90 min), t[sub ½](90-122 min), clearance (46.2-142.4 ml/min/kg), and the elimination constant (0.0057-0.0077 min⁻¹) in five test cases. In the remainder of cases, unexpected results were observed which did not allow calculation of these parameters. The plasma carbamazepine concentration was either delayed in reaching its peak concentration or it reached an apparent peak, but maintained that level for an extended period of time. It is thought that these differences between rabbits may have been due to differences in the rates of gastric emptying, a factor that may have been influenced by the food eaten by the animals in a period in excess of the 12 hours that some of the rabbits were fasted prior to the experiments. Alternatively, the time period of required sampling may have been underestimated. In addition, it is also possible that some degree of enterohepatic circulation is taking place. The relative positions of the curves for carbamazepine and for carbamazepine-10,11-epoxide suggest that there may be differences in the activities of hepatic monooxygenases and glucuronysyl transferases responsible for the metabolic fates of carbamazepine. The second set of experiments examined the influence of isoniazid and some of its principal metabolites on the conversion of carbamazepine to carbamazepine-10,11-epoxide in the S9 fraction of rat liver homogenate. This study is a prelude to planned in vivo studies of the interaction in rabbits. Three concentrations of each of isoniazid, acetyl hydrazine, acetylisoniazid, hydrazine, and isonicotinic acid were tested in a system containing constant concentrations of carbamazepine and of essential co-factors. The results indicated that there was a concentration dependent inhibition of carbamazepine metabolism by isoniazid, hydrazine, and isonicotinic acid. These types of experiments should expanded to include a range of carbamazepine concentrations so that an evaluation of the type of inhibition can be determined, as can be done Michaelis-Menton kinetics.
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