Schmidt W, Jähnchen E
J Pharmacokinet Biopharm. 1979 Dec;7(6):643-63. doi: 10.1007/BF01061212.
The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.
在雄性近交系Wistar-Lewis大鼠中，静脉注射三种形式的苯丙香豆素并长期口服苯基布他松（平均血浆浓度约为60微克/毫升）后，研究了苯基布他松与苯丙香豆素对映体及外消旋[3H]苯丙香豆素的相互作用。苯基布他松对R(+)、S(-)和R,S(+/-)苯丙香豆素的抗凝作用增强程度相似。在苯基布他松存在的情况下，对映体及外消旋苯丙香豆素血浆中的游离药物分数增加。然而，三种形式的苯丙香豆素从血浆和肝脏中的总药物消除速率以及在肝脏和血浆之间的分布几乎不受苯基布他松影响。因此，没有证据表明苯丙香豆素与苯基布他松之间存在立体选择性药物相互作用。对于外消旋[oH]苯丙香豆素，可以跟踪血浆和肝脏中游离药物的动力学以及抗凝活性的时间进程。在这些研究中，苯基布他松治疗期间血浆和肝脏中的游离药物浓度增加，但血浆和肝脏中游离外消旋苯丙香豆素的消除速率常数基本保持不变。苯基布他松显著降低了以游离药物为参考的分布容积和游离苯丙香豆素的清除率（即内在代谢清除率）。在用苯基布他松治疗的大鼠中，血浆和肝脏中总（结合和未结合）药物浓度-效应关系向左移动，但在游离药物浓度-反应关系中未观察到这种移动。总之，血浆和肝脏中苯丙香豆素游离浓度的增加以及游离药物清除率的相应降低是苯基布他松治疗后抗凝作用显著且持续增强的机制。
