Triamterene is extensively metabolized by the liver and undergoes important presystemic elimination in normal subjects after oral doses. We examined triamterene disposition in eight healthy controls and seven patients with cirrhosis and ascites. A specific and sensitive HPLC assay was used to measure concentrations of triamterene and of its major metabolite p-hydroxy-triamterene sulfate (OH-T-S). Apparent oral clearance of triamterene in controls averaged 1617 +/- 219 ml/min. Plasma concentration of OH-T-S was 7.2 +/- 1.1 times that of the parent compound (estimated by the ratio AUCOH -T-S/ AUCtriamterene ). Urinary recovery of OH-T-S accounted for 45% of the triamterene dose. There was 92% reduction in apparent oral clearance of triamterene (134 +/- 42 ml/min) in patients with cirrhosis. The ratio AUCOH -T-S/ AUCtriamterene fell to 0.55 +/- 0.2, and urinary recovery of OH-T-S accounted for only 15% of the dose. These changes in triamterene kinetics in patients with cirrhosis resulted in prolongation of its natriuretic effect, which lasted for up to 48 hr, whereas it was only 8 hr in the controls. These observations reinforce the concept that cirrhosis is associated with a markedly impaired disposition of drugs that have a large first-pass effect.