Triamterene is extensively metabolized by the liver and undergoes important presystemic elimination in normal subjects after oral doses. Triamterene disposition was examined in 8 healthy controls and 7 patients with cirrhosis and ascites. A specific and sensitive HPLC [high-performance liquid chromatography] assay was used to measure concentrations of triamterene and 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 AUC[area under the concentration-time curve]OH-T-S/AUCtriamterene). Urinary recovery of OH-T-S accounted for 45% of the triamterene dose. There was a 92% reduction in the 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 h, whereas it was only 8 h in the controls. Cirrhosis is evidently associated with a markedly impaired disposition of drugs that have a large first-pass effect.