Disopyramide protein binding in plasma from patients with nephrotic syndrome during the exacerbation and remission phases.

Abstract

1 Plasma protein binding of disopyramide was determined twice in plasma from seven patients with severe nephrotic syndrome when the disease activity was markedly different for each patient (mean ± s.d. of serum albumin 21 ± 4 vs 29 ± 3 g 1-1 (P < 0.05), proteinuria 13.6 ± 9.6 vs 2.2 ± 1.7 g day-' (P < 0.01), and oal-acid glycoprotein 0.34 ± 0.12 vs 0.95 ± 0.28 g 1-1 (P < 0.01) during the exacerbation vs remission phases, respectively).2 Plasma samples containing disopyramide at the concentrations of 0.2-12.0 P,g ml-'were analysed by ultrafiltration. The free fractions at the proposed therapeutic concentration range (2.0-6.0 ,ug ml-l) were significantly (P < 0.01) greater during the exacerbation phase than during the remission phase. 3 Multiple linear regression analysis revealed that the free fraction of disopyramide at 3.0 ,ug ml-1 correlated much better with oal-acid glycoprotein (partial correlation coefficient = 0.85, P < 0.01) than with albumin (partial correlation coefficient = 0.25, P < 0.05). 4 The binding data of disopyramide analysed by a model assuming one specific binding site and nonspecific binding(s) demonstrated that the capacity constant correlated significantly (r = 0.97, P < 0.001) with plasma aot-acid glycoprotein. 5 The results suggest that a total concentration of disopyramide within the therapeutic range may not be a reliable guide for a safe dosing scheme in patients with severe nephrotic syndrome, particularly during the exacerbation period. It is recommended that free fraction of disopyramide and/or ctl-acid glycoprotein concentration should be frequently monitored in those patients with the changing disease activity to whom this antiarrhythmic is to be prescribed.

Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers.

“…The results of the single and multiple regression analyses of the disopyramide binding data obtained from our study subjects are compatible with the established concept that AAG is implicated as the plasma protein responsible for the majority of the binding of disopyramide (Lima et al, 1981;Echizen et al, 1986Echizen et al, , 1987a and other basic drugs (Piafsky, 1980;Routledge, 1986), while albumin is mainly responsible for the binding of acidic drugs (Koch-Weser & Sellers, 1976).…”

“…The dissociation constant of the lowaffinity binding site was shown to be far exceeding the therapeutic range of disopyramide (Lima et al, 1981). The mean value of the association constant observed for the non-pregnant group was similar to that observed for the healthy subjects of both sexes (Echizen et al, 1986(Echizen et al, , 1987a. That there was a strong (r = 0.86, P < 0.01) correlation between the capacity constant and plasma AAG concentration (Figure 3 The least-squares regression line is y = 7.66-x + 0.95 (r = 0.86, P < 0.01).…”

“…Further studies are required to confirm these suggestions. Assuming that disopyramide is a useful model drug for probing alterations in the protein binding of basic drugs (Echizen et al, 1986(Echizen et al, , 1987a, our data suggest that the binding of other compounds such as lignocaine, quinidine, and tricyclic antidepressants might also be altered during and after pregnancy. This is supported by data showing that the binding of propranolol and lignocaine in maternal plasma at delivery is lower than that in plasma from non-pregnant women (Wood & Wood, 1981).…”

“…The method used to measure the protein binding of disopyramide was essentially that of Echizen et al (1986Echizen et al ( , 1987a. Aliquots of plasma (500 to 800 ,ul) spiked with disopyramide phosphate to achieve total disopyramide concentrations of 0.2, 1.0, 2.0, 3.0, 6.0, 8.0, 10.0, 12.0 ,g ml-1 (1.0 ,g ml-1 = 2.95 jxmol I-1) were ultrafiltered at 250 C using Centrifree system fitted with YMT membranes (Amicon Co., Danvers, USA).…”

“…Previous studies (Lima et al, 1981;Piafsky, 1980) have implied that, within the therapeutic plasma drug concentration range, about 90% of the protein binding of disopyramide is attributable to AAG. In addition, because disopyramide binding is saturable within the therapeutic range (Lima et al, 1981), an analysis of its binding data should provide insight into both quantitative and qualitative changes in the specific binding site of AAG for disopyramide under various clinical conditions (Echizen et al, 1986(Echizen et al, , 1987a. We have measured the plasma protein binding of disopyramide during and after pregnancy as well as in neonates, and discuss possible clinical implications of the data in interpreting concentrations of disopyramide and other basic drugs measured during routine therapeutic drug monitoring.…”