Yamada K, Yasuhara M, Yatsuzuka A, Okumura K, Sakurai T, Kawai C, Hori R
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Chem Pharm Bull (Tokyo). 1992 Jul;40(7):1876-9. doi: 10.1248/cpb.40.1876.
In order to study the mechanism of propranolol-quinidine interaction, the effects of quinidine on propranolol pharmacokinetics were examined in male Wistar rats. The concurrent oral administration of quinidine (10 mg/kg) markedly increased the plasma concentration of propranolol (2.5 mg/kg), and the area under the propranolol concentration-time curve increased about 3.6-fold. These results are consistent with previous observations in man and indicate the possible usefulness of the male Wistar rat as an animal model for investigating the mechanisms of the drug interaction. When propranolol was given intravenously, a concurrent administration of quinidine increased the apparent distribution volume of propranolol, mainly by decreasing its plasma protein binding. However, the systemic clearance of propranolol was not significantly altered by quinidine. Thus, quinidine increased the availability of oral propranolol from 13.8 +/- 2.2 to 44.2 +/- 4.6% (p less than 0.01). Furthermore, quinidine delayed the elimination of propranolol from the isolated perfused rat liver. These results indicate that quinidine reduces the presystemic elimination of propranolol in the liver, thereby increasing its systemic availability after oral administration.
为了研究普萘洛尔 - 奎尼丁相互作用的机制，在雄性Wistar大鼠中检测了奎尼丁对普萘洛尔药代动力学的影响。同时口服奎尼丁（10mg/kg）显著提高了普萘洛尔（2.5mg/kg）的血浆浓度，普萘洛尔浓度 - 时间曲线下面积增加了约3.6倍。这些结果与先前在人体中的观察结果一致，并表明雄性Wistar大鼠作为研究药物相互作用机制的动物模型可能具有实用性。当静脉注射普萘洛尔时，同时给予奎尼丁增加了普萘洛尔的表观分布容积，主要是通过降低其血浆蛋白结合率。然而，奎尼丁并未显著改变普萘洛尔的全身清除率。因此，奎尼丁使口服普萘洛尔的生物利用度从13.8±2.2%提高到44.2±4.6%（p<0.01）。此外，奎尼丁延迟了普萘洛尔在离体灌注大鼠肝脏中的消除。这些结果表明，奎尼丁减少了普萘洛尔在肝脏中的首过消除，从而增加了其口服后的全身生物利用度。
