Ducharme M P, Slaughter R L, Warbasse L H, Chandrasekar P H, Van de Velde V, Mannens G, Edwards D J
College of Pharmacy and Allied Health Professions, School of Medicine, Wayne State University, Detroit, MI 48202, USA.
Clin Pharmacol Ther. 1995 Dec;58(6):617-24. doi: 10.1016/0009-9236(95)90017-9.
To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug.
Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay.
Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter.
The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.
研究单次给予苯妥英钠和伊曲康唑，以及在先用另一种药物进行长期治疗后再给予这两种药物时它们的处置情况。
将健康男性志愿者随机分为两组并进行平行研究。第1组在两个时间点给予单次200mg口服伊曲康唑（一次单独给药，另一次在每日口服300mg苯妥英钠15天后给药）。第2组在给予伊曲康唑（每日一次200mg）15天前后分别给予单次300mg口服苯妥英钠。每次给予苯妥英钠或伊曲康唑单剂量后采集血样96小时。采用高效液相色谱法测定血清中伊曲康唑和羟基伊曲康唑浓度，采用荧光偏振免疫分析法测定苯妥英钠浓度。
苯妥英钠使伊曲康唑的浓度-时间曲线下面积（AUC）降低超过90%，从3203降至224ng·hr/ml，半衰期从22.3小时降至3.8小时。羟基伊曲康唑的AUC（从6224降至315ng·hr/ml）和半衰期（11.3小时对2.9小时）也观察到类似变化。伊曲康唑使苯妥英钠的AUC增加（10.3%；p<0.05），其他任何药代动力学参数均无变化。
伊曲康唑与苯妥英钠合用时浓度显著降低是由于代谢诱导以及伊曲康唑在此剂量下通常表现出的可饱和代谢程度降低。这种相互作用的程度可能解释了同时接受伊曲康唑和苯妥英钠治疗的真菌感染患者治疗失败的报道。
