Plasma protein binding of fentanyl

Abstract

Abstract Whole plasma of 15 normal volunteers bound 79·16% ± 0·16 s.e. (n = 45) of fentanyl, at a concentration of 0·6 ng ml−1. Measurement was by equilibrium dialysis at 37°C, pH 7·4. The largest contribution to binding appears to be due to serum albumin, since 45·52% ± 0·40 s.e. (n = 3) of fentanyl was bound to a solution of purified albumin at a concentration of 46 g litre−1 in buffer. Physiological concentrations of isolated very low density, low density and high density lipoprotein fractions in buffer bound 18·39% ± 0·65 s.e.; 39·14% ± 0·42 and 21·18% ± 0·51 (n = 15) respectively. A significant correlation was found between percent binding and serum albumin concentration (r = 0·745, P = 0·0022) and oestrogen and progestagen therapy (r = 0·766, P = 0·0014). There was no significant correlation with fasting serum cholesterol, triglyceride, age, sex or the concentration of total protein minus albumin. Binding to fibrinogen and α1-acid glycoprotein did not occur. Binding increased with increasing pH, temperature and ionic strength of the buffer. The results were compatible with hydrophobic bond formation between fentanyl and proteins. Fentanyl concentration did not affect the percent bound to whole plasma or the protein fractions over a range of 0·6 ng-10 mg ml−1. Dilution of plasma with buffer gave a linear relation of percent bound or free to log plasma dilution. The binding of fentanyl to pooled plasma of the normal subjects was not affected by a wide variety of anionic, cationic and uncharged drugs when these were tested at a concentration of 20 μg ml−1. At higher concentrations, aspirin, phenylbutazone and quinidine caused inhibition of fentanyl binding. A linear relation was found between percent bound and concentration of the inhibitory ligand. For aspirin, r = 0·873, P <0·01; for phenylbutazone, r = 0·81, P <0·05; and for quinidine, r = 0·982, P <0·01. Aspirin and phenylbutazone inhibited binding of fentanyl to albumin, while quinidine caused inhibition of binding to lipoproteins of all three densities, but not to albumin. Changes in the concentrations of the common ions of plasma (except H+), of free fatty acids and of creatinine did not affect fentanyl binding to whole plasma. 8 M urea reduced binding by 25% of the normal value.