Nonfatty acid-modulated variations in drug binding due to heparin.

Changes in free fatty acids (FFAs) do not always correlate with variations in drug binding. To dissociate heparin effects on FFAs and drug binding, six healthy fasting subjects received 50 units (USP) IV heparin (Harris L932) with and without protamine (3.2 mg IV). Protamine completely suppressed heparin-induced rises in FFAs and warfarin free fraction (W alpha), but diazepam free fraction (D alpha) increased (P less than 0.005). In vitro, increasing concentrations of heparin added to serum increased D alpha (P less than 0.0005) and W alpha (P less than 0.005) without changing FFAs. In eight subjects given 50 units IV heparin (Harris L014), FFAs (P less than 0.001) and propranolol free fraction (P alpha) rose (P less than 0.01), but variations in FFAs and P alpha did not correlate (r = 0.18). When two different heparin lots (Harris L014 and Organon LA39) were tested in vivo. Harris L014 heparin increased FFAs (P less than 0.005) and P alpha (P less than 0.0005), but variations in FFAs and P alpha correlated poorly (r = 0.43, P less than 0.05). In contrast, the Organon LA39 heparin did not change FFAs, but did increase P alpha (P less than 0.0005); variations in FFAs and P alpha did not correlate (r = 0.22). These results indicate that heparin-induced variations in drug binding are not exclusively related to changes in FFAs.

Variability in heparin effect on serum drug binding.

Heparinized saline was given to seven men and one woman, aged 21 to 42 yr, after a 14-hr fasting period and 2 hr after breakfast; blood was collected in nonoheparinized tubes. Diazepam (D alpha) and warfarin (W alpha) free fractions were determined in serum by equilibrium dialysis to which radiolabeled drug was added. After 50 U heparin (Harris LO14) intravenously, the maximum effect on D alpha, W alpha, and free fatty acids (FFA) developed in 5 min and lasted 20 to 30 min. D alpha rose and W alpha fell (p < 0.01) at 5 min. Cumulative doses of heparin increased FFAs (F4,16 = 18.29, p < 0.0005). D alpha rises (r = 0.73, p < 0.001) and W alpha falls (r = -0.74, p < 0.001) correlated with changes in FFAs. D alpha rises and W alpha falls were greater postprandially than in the fasted state (p < 0.01). Five subjects were randomly assigned up to 400 U intravenously of each of two different heparin lots (Harris LO14, and Organon LA39.) The FFA rises (reflecting heparin lipolytic activity, F1,32 = 179.62, p < 0.0005), D alpha rises (F1,32 = 34.22, p < 0.0005), and the W alpha falls (F1,32 = 33.20, p < 0.0005) by heparin Harris LO14 were greater than those by heparin Organon LA39. Although small doses of heparin, such as those in heparin locks, can affect drug binding, the extent and variability of the effect depends on the biologic activity of the heparin, and varies with manufacturer and lot, exact time of sampling, and eating.