Comparative Pharmacokinetics of Unbound Disopyramide Enantiomers following Oral Administration of Racemic Disopyramide in Humans

Abstract

To the Editor: A previous study has reported a higher total clearance (CLt) and renal CL (CLr), a longer half-life (t1/2), and a larger apparent volume of distribution (Vd) for R(−)-disopyramide (D) compared with S( +)-D following the administration of racemic D, whereas no differences in these pharmacokinetic parameters were observed between the enantiomers following separate administration. As a possible explanation for these distinct pharmacokinetic properties following racemic D dosing, in vivo plasma protein binding interaction between the two enantiomers has been suggested. However, the protein binding data of D enantiomers have been obtained only after in vitro spiking or after administration of individual enantiomers. To date, no data on the plasma protein binding of D enantiomers following administration of racemic D are available to our knowledge, except our preliminary study which obtained data from only one subject. However, the binding parameters using plasma samples taken serially after administration of racemic D might be different from those obtained after an in vitro study because of possible in vivo binding interactions not only between the two enantiomers of D, but also between enantiomers of D and its main metabolite in humans [mono-N-dealkyl D (MND)], in addition to interindividual variability of plasma D binding. In our recent study, an almost threefold increase in the unbound fraction (fu) at 1.0 μg/mL of S( + )-D was predicted in the presence of 0.5 μg/mL of unbound (+ )-MND, compared with the fu for S( + )-D alone in an in vitro study. Therefore, we decided to administer racemic D and examine whether such in vivo plasma protein binding interactions between D enantiomers and/or between enantiomers of D and MND indeed exist, and whether they result in the difference in pharmacokinetics between D enantiomers when D is given as a racemic mixture. The purpose of the present study was to compare the total and unbound pharmacokinetic parameters of D enantiomers after racemic D dosing and to clarify the factor(s) affecting the distinctive pharmacokinetics observed between the two enantiomers.