The artifactual nature of heparin-induced drug protein-binding alterations.

Our purpose was to determine whether the reported alteration of protein drug binding after heparin administration in man was artifactual as a result of continued in vitro activity of triglyceride lipases. The lipoprotein lipase inhibitors protamine (14 mg/ml) and ethylenediaminetetraacetic acid (10 mg/ml) were added to blood samples from 11 healthy subjects before and 15 min after 100 USP units of intravenous heparin. Heparin elevated total nonesterified fatty acid (NEFA) concentration (P less than 0.001) and free fractions of lidocaine, diazepam, and propranolol (P less than 0.001 for all). The presence of the lipase inhibitors diminished the heparin-induced elevation of NEFA (P less than 0.001) and free fractions of lidocaine (P less than 0.001) and diazepam (P less than 0.001), but these values were still greater than control. The inhibitors reduced propranolol binding in control samples and did not diminish the effects of heparin. The change in NEFA concentrations correlated with the free fraction changes of all three ligands (r = 0.739 to 0.849). These data suggest that the heparin-induced protein binding changes are to, a large extent, in vitro artifacts.