Rengelshausen Jens, Göggelmann Christoph, Burhenne Jürgen, Riedel Klaus-Dieter, Ludwig Jochen, Weiss Johanna, Mikus Gerd, Walter-Sack Ingeborg, Haefeli Walter E
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Br J Clin Pharmacol. 2003 Jul;56(1):32-8. doi: 10.1046/j.1365-2125.2003.01824.x.
A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.
In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.
Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin.
Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.
早期报告提示强心苷地高辛与抗生素克拉霉素之间存在具有临床重要意义的相互作用。本研究旨在调查这种相互作用的程度以及不同机制的相对贡献。
采用随机、安慰剂对照、双盲交叉设计，对12名健康男性单次口服0.75 mg地高辛，并同时口服安慰剂或每日2次、每次250 mg克拉霉素，共3天。此外，3名受试者接受单次静脉注射0.01 mg·kg⁻¹地高辛，并同时口服安慰剂或克拉霉素。用地高辛血浆和尿液浓度的高灵敏度放射免疫分析法进行测定。
口服克拉霉素导致地高辛血浆浓度-时间曲线下面积增加1.7倍[平均AUC(0,24)±标准差23±5.2对14±2.9 μg·L⁻¹·h；差异的95%置信区间(CI) 7.0, 12；P = 0.002]，并使地高辛的非肾小球肾清除率降低[平均ClRng(0, 24)±标准差3,4±39对57±41 mL·min⁻¹；差异的95% CI 7.2, 45；P = 0.03]。在克拉霉素吸收期，服用和未服用克拉霉素时地高辛血浆平均浓度之比最高。静脉注射后，在同时服用克拉霉素期间，地高辛AUC(0,24)仅增加1.2倍。
地高辛口服生物利用度增加和非肾小球肾清除率降低均促成了地高辛与克拉霉素之间的相互作用，这可能是由于肠道和肾脏P-糖蛋白受到抑制所致。
