Matsumura Y, Yokota M, Yoshioka H, Shibata S, Ida S, Takiguchi Y
Department of Clinical Pharmacology, University of Tokushima, Faculty of Pharmaceutical Sciences, Japan.
J Int Med Res. 1999 Jul-Aug;27(4):167-75. doi: 10.1177/030006059902700402.
It has been reported that prothrombin time (PT), which is prolonged by warfarin, is reduced when patients on warfarin also take griseofulvin repeatedly. We investigated the cause of the drug interaction and the initial effects of griseofulvin on warfarin pharmacokinetics. Total cytochrome P-450, and the activities of aminopyrine N-demethylase, aniline p-hydroxylase and 7-ethoxycoumarin O-deethylase, after repeated administration of griseofulvin (100 mg/kg orally daily for 5 days) were examined. Acute effects of single doses of griseofulvin (100 mg/kg) on coagulation activity (prothrombin time) and warfarin pharmacokinetics after administration of warfarin were also studied. Repeated administration of griseofulvin induced warfarin-metabolizing enzymes. In contrast, a single administration of griseofulvin increased prothrombin time and serum warfarin concentrations. The activity of a warfarin-metabolizing enzyme (7-ethoxycoumarin O-deethylase) was reduced when griseofulvin was added to rat liver microsomes. The results suggest that reduced warfarin action after repeated administration of griseofulvin may be due to induction of warfarin-metabolizing enzymes, but that there is also an initial increase in warfarin action.
据报道，华法林可使凝血酶原时间（PT）延长，但服用华法林的患者同时反复服用灰黄霉素时，凝血酶原时间会缩短。我们研究了药物相互作用的原因以及灰黄霉素对华法林药代动力学的初始影响。在反复给予灰黄霉素（每日口服100mg/kg，连续5天）后，检测了总细胞色素P-450以及氨基比林N-脱甲基酶、苯胺p-羟化酶和7-乙氧基香豆素O-脱乙基酶的活性。还研究了单剂量灰黄霉素（100mg/kg）对华法林给药后凝血活性（凝血酶原时间）和华法林药代动力学的急性影响。反复给予灰黄霉素可诱导华法林代谢酶。相反，单次给予灰黄霉素会延长凝血酶原时间并提高血清华法林浓度。当向大鼠肝微粒体中加入灰黄霉素时，华法林代谢酶（7-乙氧基香豆素O-脱乙基酶）的活性降低。结果表明，反复给予灰黄霉素后华法林作用减弱可能是由于华法林代谢酶的诱导，但华法林作用也会有初始增强。
