The widely used analgesic propoxyphene is subject to extensive presystemic (first-pass) biotransformation after oral administration. There have been indications that presystemic biotransformation of a drug may be less in anephric patients than in healthy subjects. Plasma concentrations of propoxyphene (a drug with dangerous adverse effects at high concentrations) and its major and pharmacologically active metabolite norpropoxyphene have been compared in 7 anephric patients and 7 healthy subjects after oral administration of a 130-mg dose. Maximum propoxyphene concentrations were much higher (177 +/- 16 vs 81 +/- 35 ng/ml, mean +/- SD, p less than 0.001), and areas under the concentration-time curve over 12 hr were much larger (4,310 +/- 1,520 vs 2,250 +/- 1,050 ng hr/ml, p less than 0.02) in the anephric patients than in the normal subjects. These differences were statistically significant even after normalization for dose per body weight. Norpropoxyphene concentrations were also higher and more persistent in the anephric patients. These differences, which appear to result from decreased presystemic biotransformation of propoxyphene and decreased elimintation of norpropoxyphene, indicate that propoxyphene should be used cautiously and at reduced doses in patients with renal failure.