Propafenoneと5-hydroxypropafenoneの血漿濃度と抗心室性不整脈効果との関係

Plasma Concentrations of Propafenone and 5-hydroxypropafenone and their Relationship to the Efficacy against Ventricular Arrhythmia

　propafenone（PF）の薬物動態や薬物力学に関する過去の多くの知見は，肝cytochrorneP−450の酵素活性が著しく低下している人を含む白人を対象とした結果である．このため，PFと50-hydroxypropafenone（5-HP）の血漿濃度には個人差が著しく，しかもそれらの濃度間に相関はなく，それらの濃度と抗不整脈効果との相関も認められていない．われわれは，上記酵素活性が低下していない日本人におけるPFと5-HPの血漿濃度の相関や，それらの濃度と抗心室性不整脈効果との関係について検討し，過去の海外における成績と比較した．4,000／日以上の心室性期外収縮（PVC）のある患者22名を対象にpropafenone（PF）150mgを食後3回投与し，投与2時間後のPFと5-hydroxypropafenone（5-HP）の血漿濃度を測定した．PFの抗不整脈効果は，PF投与前後に24時間Holter心電図を施行し，1日PVC頻度の減少率から評価した．

　PF投与後のPVCの平均減少率は75.6％であった．PFと5-HPの血漿濃度はそれぞれ29-1,033ng／ml［347±291（標準偏差）］，27-351ng／ml（132±81）の広範囲にあり，PFと5-HPの血漿濃度には直線相関を認めた．PFあるいは5-HPの血漿濃度とPVC減少率との間には全体として相関はなかったが，PVC減少率が濃度依存性に直線相関する群と，血漿濃度とは無関係に80％以上の高いPVC減少率を示す群に分類し得た．PFと5-HPの血漿濃度に直線相関をみたのは，白人に比べて邦人における肝cytochrome P−450の活性に個人差が少ないためと考えられた．PFと5-HPの低い血漿濃度で高いPVC抑制率を示したことは，PFの抗不整脈効果には薬剤血漿濃度のみでなく，おそらく心筋の薬剤感受性も関与すると思われた．

Caucasian population includes 7 to 10% of poor metabolizers for propafenone (PF) due to an absence of hepatic cytochrome P-450 enzyme. Earlier studies on Caucasian population have demonstrated no positive correlation between plasma concentrations of propafenone (PF) and 5-hydroxypropaphenone (5-HP) and no clear relationship between the concentrations and the anti-arrhythmic efficacy of PF. To delineate those relationships in Japanese population in which no poor metabolizers are included, consecutive 22 patients with premature ventricular complexes (PVCs)＞4000/ day and without organic heart disease were studied. As the efficacy of PF against ventricular arrhythmia a percent reduction in daily frequency of PVCs was evaluated from mandatory 24-hour Holter monitoring before and after the postprandial administration of PF with 450 mg/day. The plasma concentrations of PF and5-HP were determined in the blood collected 2 hours after the administration of PF.

The mean percent reduction in the daily frequency of PVCs after the therapy with PF was 75.6%. The plasma concentration of PF ranged widely from 29-1033 ng/ml (347±291ng/ml, mean±SD) and that of 5-HP ranged from 27-351ng/ml (132±81 ng/ml). A linear relation with Y=0.25X +45.498 was found between the plasma concentrations of PF and 5-HP. Two distinctly different groups were noted in the relationship between the plasma concentrations of PF and 5-HP and the percent reduction in the daily frequency of PVCs. One group showed＞80% reduction in PVCs, regardless of the plasma concentrations of PF and 5-HP. The other group showed a linear relation between the percent reduction in PVCs and the plasma concentrations of PFand 5-HP.

The linear correlation between the plasma concentra-tions of PF and 5-HP is likely due to an absence of poor metabolizers and probably homogeneous activity of hepatic cytochrome P-450 enzyme in Japanese popula-tion. The presence of distinguished two groups on the relationship between the plasma concentrations and the anti-arrhythmic efficiency of PF implicated that anti-arrhythmic efficiency of PF depends on not only plasma concentrations of PF and 5-HP but possibly on the variation of cardiac sensitivity to PF and 5-HP.