不整脈患者におけるＤｉｓｏｐｙｒａｍｉｄｅ光学異性体のＰｏｐｕｌａｔｉｏｎ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ解析と蛋白結合および抗不整脈効果との関連性

Abstract

Disopyramide (DP) is used widely as an antiarrhythmic agent. The antiarrhythmiceffects of DP's enantiomers vary, and its metabolism and protein binding are alsostereoselective. Population pharmacokinetic parameters of the disopyramide racemate (DP), enantiomers [S (+)-DP, R (-)-DP], and their unbound concentrations [uDP, S (+)-uDP, and R (-)-uDP] were analyzed using the NONMEM program (Nonlinear Mixed Effects Model). Data were available from 108 points of 33arrhythmic patients onmaintenance therapy of disopyramide racemate .We evaluated the factors, to whichpharmacokinetic parameters are attributed. We also studied the relationships betweenserum concentration [DP, S (+)-DP, R (-)-DP, uDP, S (+)-uDP, and R (-)-uDP] andthe arrhythmic effect.The data were fitted to the 1-compartment model using NONMEM Ver IV.For DP, S (+)-DP, and R (-)-DP, elimination constants (ke) were estimated as 0.0648, 0.0663, and 0.0691h-1, respectively, and apparant distribution volumes (Vd/F) were estimatedas63.2, 54.1, and 71.6 L, respectively. For unbound disopyramide [uDP, S (+)-uDP, andR (-)-uDP], ke were estimated to be 0.100, 0.104, and 0.0990h-1, and Vd/F were estimated as 181, 206, and 161 L, respectively. Using the ke, and Vd/F values which wereestimated by NONMEM, typical dosing (100 mg tid, or 100 mg bid) time-concentrationcurves were well fitted to the observed data.Unbound fractions of both DP enantiomers showed nonlinearity and the bindingratio of S (+)-DP was 0.84±0.07.This binding ratio was higher than that of R (-)-DP [0.70±0.11 (p<0.01)].Unbound fractions of both DP enantiomers correlated with α1-acid glycoprotein (AGP) (p<0.01), but did not correlate with total protein or albumin.On the other hand, using NONMEM, a significant proportion of the variability of Vd/Fcould be attributed to AGP (p<0.001), but not to body weight, gender, serum creatinine, total protein, or albumin. NONMEM could clarify the pharmacokinetic features in theprotein binding of disopyramide. For DP, intra-individual variability of Vd/F wasreduced from 32.9% in the simple model to 27.2% in the final model in which Vd/Fincludes AGP.Individual steady state concentrations were estimated by NONMEM using theBayesian method. The average total concentrations of racemate and both enantiomers in9responders were similar to 4non responders. The average unbound concentrations ofall 9responders were higher than those of the 4 non responders, even though there wasno significant difference. Unbound concentrations may reflect drug concentrations in thetissue, which suggests that unbound concentrations may indicate the antiarrhythmiceffect rather than the total concentration.