Sulfadimidine and isoniazid loading in man and laboratory rats. Pharmacokinetic and pharmacogenetic results on drug acetylation.

Drug acetylation polymorphism is of clinical importance in slow and rapid acetylators. There are therapeutic and toxic consequences of interindividual drug acetylation of, e.g. isoniazid, procainamide and various sulfonamides. For comparing pharmacokinetic and pharmacogenetic data it is necessary to establish a useful model in experimental animals: 1. We determined the half-lives of isoniazid and sulfadimidine in man and rats using a simple loading test and we compared these data with those of in vitro acetylation. In man the half-lives of both substances correlate very well and correspond to acetylation values in vitro. 2. There is no sufficiently good correlation of sulfadimidine concentration in blood and saliva. Furthermore we found no strict correlation between drug concentration in venous and capillary blood. This should be should be considered in pharmacogenetic research. 3. The sulfadimidine half-lives in male Sprague-Dawley and Wistar rat are similar. Both half-lives and acetylation rates in vivo are normally distributed. Sulfadimidine half-lives and the rate of acetylation in vitro do not correlate. Compared with human values the investigated rats are rapid acetylators. Young rats reach their total acetylation capacity in vivo 65 days post partum. 4. Many organs of the rat acetylate sulfadimidine (kidney, lung, intestinal mucosa) with the exception of the spleen. 5. Excess substrate inhibits acetylation of sulfadimidine in vitro. Results of further inhibition studies suggest two or more N-acetyltransferases. 6. Isoniazid inhibits the sulfadimidine acetylation in rat liver homogenates and vice versa. To sum up all data, Sprague-Dawley and Wistar rats seem to be a useful model for human sulfadimidine metabolism pharmacokinetic and, in part, pharmacogenetic studies. Furthermore drug analysis in human saliva can be helpful in pharmacogenetic and pharmacokinetic research in the future.