Pharmacokinetics of an ACE inhibitor, S-9780, in man: evidence of tissue binding.

Pharmacokinetic data from 20-min constant rate infusions of the ACE inhibitor S-9780 1 mg to 16 subjects were studied for evidence of nonlinearity. A hierarchy of standard compartmental models and of nonlinear binding models was fitted to the data by least squares nonlinear regression and the most appropriate model was chosen on the basis of F-ratio tests, Schwarz criteria, and residual plots. A one-compartment model which included saturable tissue and plasma binding components allowed the best overall description of the data. Median parameter estimates from this model suggest that approximately 308 nmol of plasma binding sites and 572 nmol of tissue binding sites were present and that the total plasma concentration of S-9780 at 50% saturation of binding sites was 16.5 nmol L-1. The elimination half-life for free drug in plasma was only 30 min. This model describes the discrepancy previously noted between accumulation and apparent elimination half-lives for long-acting ACE inhibitors and offers a noninvasive method for assessment of tissue-bound ACE inhibitor in vivo.