Plasma binding of disopyramide and mono-N-dealkyldisopyramide.

1 Measuring total plasma levels of disopyramide (DP) and the main metabolite mono-N-dealkyldisopyramide (MND) in patients on maintenance therapy with DP has shown concentrations of MND comparable with those of DP, with wide intersubject variations. 2 A method which permits simultaneous measurement of unbound fraction of DP and MND has been developed. 3 In healthy subjects the unbound fraction of both DP and MND was concentration dependent, i.e. increased with higher concentrations of DP or MND. 4 The plasma protein binding of DP is altered by varying concentrations of MND. Clinically relevant concentrations of MND may increase the unbound fraction of DP approximately twofold. 5 The plasma protein binding of MND is also altered by varying concentrations of DP. Variation in the concentration of DP from the lower to the upper part of the therapeutic range may cause a 1.5-fold increase in the unbound fraction of MND. 6 In the assumed therapeutic range of 6-15 mumol DP/L, the interpatient variance of unbound DP concentration might be ten-fold or even higher. The present findings indicate the need for monitoring unbound drug concentrations in any attempt to establish plasma concentration/effect relationship.