Erythrocyte binding and plasma protein binding of codeine in sickle cell patients and healthy controls were determined. A reversed-phase HPLC procedure was used for codeine analysis. Codeine was extracted from alkalinized plasma, separated on a CN column, and assayed by fluorescence detection. The erythrocyte-buffer partition coefficient was significantly higher in sickle cell patients (1.72 +/- 0.21) than in healthy controls (1.25 +/- 0.14). No time dependence of partitioning was observed. The fraction of codeine bound to plasma proteins, determined by ultrafiltration, was significantly higher in sickle cell patients (66.0% +/- 8.6%) than in healthy controls (30.5% +/- 2.7%). No concentration dependence of erythrocyte or protein binding was observed. Further studies were performed to elucidate the binding mechanisms. From a ghost cell binding study it was concluded that the major binding sites for codeine are in the cell membrane. A decrease in codeine binding was observed in the presence of bilirubin. Codeine binding to alpha 1-acid glycoprotein was found to be minimal. The levels of alpha 1-acid glycoprotein and other glycoproteins in sickle cell patients and healthy controls were measured by glycoprotein electrophoresis. The results showed no significant difference between the two groups. Plasma protein electrophoresis was performed for the two groups. The results showed a significant difference in gamma-globulin levels between sickle cell patients and healthy controls. Codeine is known to bind to gamma-globulin, a fact that may explain in part the observed increase in the plasma protein binding of codeine in sickle cell patients.(ABSTRACT TRUNCATED AT 250 WORDS)