PLASMA-PROTEIN BINDING OF QUININE - BINDING TO HUMAN SERUM-ALBUMIN, ALPHA-1-ACID GLYCOPROTEIN AND PLASMA FROM PATIENTS WITH MALARIA

The binding of quinine to human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and plasma obtained from healthy subjects (10 caucasians and 15 Thais) and from Thai patients with falciparum malaria (n = 20) has been investigated. In healthy volunteers, plasma protein binding expressed as the percentage of unbound quinine was 7.9-31.0% (69-92.1% bound). The mean percentage of unbound quinine found with essentially fatty acid-free HSA (40 g L-1) was 65.4 +/- 1.5% (mean +/- s.d.) and was comparable with the value (66.3 +/- 3.8%, mean +/- s.d.) for Fraction V HSA (40 g L-1). This suggests that fatty acids do not influence the plasma protein binding of quinine. Binding of quinine to 0.7 g L-1 AAG was high (mean unbound 61.0 +/- 5.0%), indicating that quinine is bound primarily to AAG and albumin, although other plasma proteins such as lipoproteins may be involved. The mean percentage of unbound quinine was slightly less in caucasians (14.8 +/- 6.7% unbound), compared with healthy Thai subjects (17.0 +/- 6.7% unbound). The higher binding of quinine in caucasian subjects was associated with a higher plasma AAG concentration observed in caucasians. Mean percentage of unbound quinine was significantly lower in Thai patients with malaria (10.9 +/- 4.0%) than in the healthy Thai subjects. The increase in the extent of quinine binding corresponded wi h the increase in the acute-phase reactant protein, AAG in the patients with malaria. Overall, when the data were combined there was a significant correlation (r = 0.846, P < 0.005) between the binding ratio (bound/unbound) of quinine and the plasma AAG concentration. This suggests that plasma AAG concentration may serve as a useful index to predict alterations in quinine binding. Although quinine is bound to albumin, it was not bound to either site I or site II on HSA as indicated from equilibrium dialysis and fluorescent probe displacement studies. Binding displacement studies revealed that there was no marked displacement of quinine by a variety of highly bound acidic and basic drugs, including other antimalarial drugs at their therapeutic concentrations.