Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 microgram/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1, indicating that TEA is localized in these tissues. In vitro tissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constitutents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occured with 5-15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.

The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t 1/2 beta) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given orally, the area under the plasma concentration-time curve (AUC) and a systemic availability (theta) in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed theta in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acid-labile metabolites was similar to the t 1/2 beta of H. The AUCs for metabolies were 4--12 times larger than for the parent drug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective of routes of administration or the acetylator status.