Relationship between alpha 1‐acid glycoprotein and plasma binding of disopyramide and mono‐N‐dealkyldisopyramide.

Abstract

Highly purified serum albumin did not bind either disopyramide (DP) or mono‐N‐dealkyldisopyramide (MND). The unbound fraction of DP and MND in highly purified serum alpha 1‐acid glycoprotein (AAG) at 0.5 g/l was 57 and 62 and at 2.0 g/l 19 and 30% respectively. Unbound DP and MND were measured in spiked plasma (10 mumol/l of DP or MND), from 60 patients, having AAG concentrations varying from 0.4 to 3.0 g/l. Unbound drug varied from 13 to 58 and from 24 to 62% for DP and MND, respectively, and was inversely related to the plasma concentration of AAG (r = ‐ 0.9016, r = ‐0.9157). A linear relationship was found between the binding ratio (moles bound divided by moles unbound) and the plasma concentration of AAG for both DP (r = 0.9199) and MND (r = 0.9270), whereas no relationship was found between the binding ratios of DP or MND and the plasma concentrations of total protein, albumin, haptoglobin, alpha 1‐antitrypsin or the immunoglobulins IgG, IgA or IgM. In patients on DP maintenance therapy, a linear relationship was found between percent unbound DP and the plasma concentration of DP in samples with similar AAG concentrations. Furthermore, a linear relationship was found between the binding ratio of DP and the plasma concentration of AAG in samples with similar DP concentrations. The present findings support the concept that AAG is the major serum protein responsible for the binding of DP and MND.

Relationship between alpha 1‐acid glycoprotein and distribution of disopyramide and mono‐N‐dealkyldisopyramide in whole blood.

“…David et al (1983) further demonstrated prolonged variability in plasma protein binding in vitro from 20 patients with acute myocardial infarction with a relationship between the unbound DP fraction and plasma AAG concentration. The relationship between the binding of DP and the plasma AAG concentration was also demonstrated by Bredesen & Kierulf (1984) and Haughey et al (1985). Bredesen & Kierulf (1984) found a linear relationship between the AAG concentration and the binding ratio in plasma spiked samples.…”

“…The relationship between the binding of DP and the plasma AAG concentration was also demonstrated by Bredesen & Kierulf (1984) and Haughey et al (1985). Bredesen & Kierulf (1984) found a linear relationship between the AAG concentration and the binding ratio in plasma spiked samples. As for the plasma spiked samples a linear relationship was also found between the AAG concentration and the binding ratio in plasma from whole blood spiked samples.…”

“…(Aitio 1981;Bredesen et al, 1982;David et al, 1983). Two recent studies indicated that al-acid glycoprotein (AAG) was the major protein, and probably the only one responsible for the binding of DP and MND (Pike et al, 1983;Bredesen & Kierulf, 1984). AAG is an acute phase protein and its plasma concentration rises in various diseases states (Fremstad et al, 1976;Piafsky et al, 1980;David et al, 1983;Lunde et al, 1986).…”

“…Previous work demonstrated that disopyramide binds mainly to the acute-phase protein, a1-acid glycoprotein (AAG) (Lima et al, 1981;David et al, 1983). A recent study, however, indicated that AAG is probably the only protein responsible for the binding of DP and MND, and that measurement of the AAG concentration together with both the DP and MND concentration could be used to predict the unbound, pharmacologically active, concentration of DP (Pike etal., 1983;Bredesen & Kierulf, 1984). Since AAG is an acute phase reactant large variations in drug plasma concentration will occur during various disease states associated with a variation in the binding of DP and MND.…”

The influence of age and smoking on the elimination of disopyramide.

“…This age related decrease in total clearance of disopyramide can be explained by the well known age reduction in renal function (Kampmann et al, 1974) as disopyramide is excreted unchanged in the urine to an extent of about 50% (Hinderling & Garrett, 1976). Like many other basic drugs (Piafsky & Borgfa 1977;Piafsky etal., 1978) disopyramide is bound to al-acid glycoprotein in plasma (Lima et al, 1981;Bredesen & Kierulf, 1984). al-acid glycoprotein is an acute phase reactant of a heterogenous composition (Hansen et al 1984) known to increase non-specifically in response to acute stress including acute myocardial infarction (David et al, 1983).…”