Isohanni M H, Neuvonen P J, Palkama V J, Olkkola K T
Department of Anaesthesia, University of Helsinki, HYKS, Finland.
Eur J Clin Pharmacol. 1998 Sep;54(7):561-5. doi: 10.1007/s002280050513.
We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design.
The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg x kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography.
The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0-11 h) by 45-60%.
The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine.
我们采用随机交叉研究设计，在9名健康志愿者中研究了细胞色素P450 3A4同工酶（CYP3A4）的两种抑制剂红霉素和伊曲康唑与静脉注射利多卡因之间可能的相互作用。
受试者口服安慰剂、红霉素（每日3次，每次500mg）或伊曲康唑（每日1次，每次200mg），共4天。在使用安慰剂、红霉素或伊曲康唑预处理的第4天，静脉输注1.5mg·kg-1利多卡因，持续60分钟。定时采集血浆样本直至11小时。利多卡因及其代谢产物单乙基甘氨酰二甲苯胺（MEGX）的浓度通过气相色谱法测定。
在所有三个阶段，利多卡因浓度-时间曲线下面积相似，但与安慰剂相比，红霉素使利多卡因的消除半衰期从2.5小时显著延长至2.9（0.7）小时。服用伊曲康唑后，t1/2为2.6小时。在所有阶段，稳态时的血浆清除率和分布容积值相似。与安慰剂和伊曲康唑相比，红霉素使MEGX峰值浓度显著增加约40%，AUC(0-11 h)增加45-60%。
静脉注射利多卡因的血浆衰减实际上不受同时给予红霉素和伊曲康唑的影响。然而，红霉素会增加MEGX的浓度，这表明红霉素要么增加了通过N-去乙基化代谢的利多卡因的相对量，要么减少了MEGX的进一步代谢。有必要进一步研究以阐明在长时间静脉输注利多卡因期间，红霉素诱导的MEGX浓度升高的临床意义。
