Vincent J, Hunt T, Teng R, Robarge L, Willavize S A, Friedman H L
Department of Clinical Research, Pfizer Central Research, Groton, Connecticut 06340, USA.
Am J Surg. 1998 Dec;176(6A Suppl):32S-38S. doi: 10.1016/s0002-9610(98)00218-9.
Morphine and antibiotics are frequently coadministered in the surgical setting. These agents may interact, reducing the efficacy of the antibiotic or increasing the toxicity of morphine. It is therefore important to determine whether antibiotics that might be used for surgical prophylaxis have the potential to change the pharmacokinetics of morphine. It is equally important to learn whether morphine affects the plasma levels of antibiotics and thus may potentially influence their efficacy or tolerability.
This open, randomized, placebo-controlled, three-treatment, three-period cross-over study enrolled 19 healthy volunteers. Oral trovafloxacin (200 mg), a novel fluoroquinolone antibiotic, and intravenous morphine (0.15 mg/kg) were coadministered, and the effects on the pharmacokinetics of each drug and on changes in the pharmacologic action of morphine, estimated from its effects on respiratory rate and level of sedation, were examined.
When trovafloxacin was coadministered with morphine, the half-life of trovafloxacin was unchanged; however, the ratio of the area under the serum concentration versus time curve (AUC(0-infinity)) estimates for trovafloxacin/morphine versus trovafloxacin/placebo was 63.8% (95% confidence interval [CI], 40.7% to 100.3%), indicating a 36% reduction in the bioavailability of trovafloxacin. The ratio of the mean maximum serum concentration (Cmax) estimates of trovafloxacin for the two treatments was 53.8% (95% CI: 36.1% to 80.1%), indicating a 46% reduction in Cmax. The time to Cmax was delayed by 4 hours. With trovafloxacin coadministration, there were no statistically significant changes in either the mean relative bioavailability of morphine or that of its metabolite, 6beta-glucuronide-morphine. Coadministration of trovafloxacin did not exacerbate the reduction in respiratory rate or increase the number of side effects associated with morphine administration.
Coadministration of trovafloxacin and morphine reduces the bioavailability and maximum serum concentrations of trovafloxacin. However, elimination of oral trovafloxacin is not impaired, suggesting that the efficacy of trovafloxacin could be maintained in many patients who receive concomitant morphine. Morphine plasma levels and pharmacologic effects are not significantly altered by coadministration of trovafloxacin. Despite their similar metabolic pathways, the trovafloxacin/morphine combination neither exacerbates the respiratory depressant effects of morphine nor increases the frequency of side effects when compared with placebo/morphine treatment. These results suggest that the efficacy of trovafloxacin may be maintained when coadministered with morphine. Concurrent administration of trovafloxacin and morphine is unlikely to alter the pharmacologic effects of morphine.
在外科手术环境中，吗啡和抗生素经常联合使用。这些药物可能会相互作用，降低抗生素的疗效或增加吗啡的毒性。因此，确定可能用于外科预防的抗生素是否有可能改变吗啡的药代动力学非常重要。了解吗啡是否会影响抗生素的血浆水平，从而可能影响其疗效或耐受性同样重要。
这项开放、随机、安慰剂对照、三治疗、三周期交叉研究纳入了19名健康志愿者。联合给予口服曲伐沙星（200毫克），一种新型氟喹诺酮类抗生素，和静脉注射吗啡（0.15毫克/千克），并检查其对每种药物药代动力学的影响以及根据其对呼吸频率和镇静水平的影响估计的吗啡药理作用变化。
当曲伐沙星与吗啡联合使用时，曲伐沙星的半衰期未改变；然而，曲伐沙星/吗啡与曲伐沙星/安慰剂的血清浓度-时间曲线下面积（AUC(0-无穷大)）估计值之比为63.8%（95%置信区间[CI]，40.7%至100.3%），表明曲伐沙星的生物利用度降低了36%。两种治疗的曲伐沙星平均最大血清浓度（Cmax）估计值之比为53.8%（95%CI：36.1%至80.1%），表明Cmax降低了46%。达到Cmax的时间延迟了4小时。联合使用曲伐沙星时，吗啡及其代谢物6β-葡萄糖醛酸吗啡的平均相对生物利用度均无统计学显著变化。曲伐沙星联合给药并未加剧呼吸频率的降低或增加与吗啡给药相关的副作用数量。
曲伐沙星与吗啡联合使用会降低曲伐沙星的生物利用度和最大血清浓度。然而，口服曲伐沙星的消除未受损害，这表明在许多接受吗啡的患者中曲伐沙星的疗效可能得以维持。曲伐沙星联合给药不会显著改变吗啡的血浆水平和药理作用。尽管它们的代谢途径相似，但与安慰剂/吗啡治疗相比，曲伐沙星/吗啡组合既不会加剧吗啡的呼吸抑制作用，也不会增加副作用的发生率。这些结果表明，曲伐沙星与吗啡联合使用时其疗效可能得以维持。曲伐沙星和吗啡同时给药不太可能改变吗啡的药理作用。
