Penson Richard T, Joel Simon P, Roberts Michael, Gloyne Anna, Beckwith Stephen, Slevin Maurice L
Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE.
Br J Clin Pharmacol. 2002 Apr;53(4):347-54. doi: 10.1046/j.1365-2125.2002.01554.x.
Morphine-6-glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio-respiratory effects of three alternative routes of administration of M6G.
Ten healthy volunteers participated in an open randomized study. Subjects received M6G 2 mg as an intravenous bolus, 20 mg orally, 2 mg subcutaneously and 4 mg by the nebulized route. Pulse, blood pressure, respiratory rate and peak flow rate were monitored and subjective toxicity recorded on rating and visual analogue scales.
After i.v. M6G the mean (+/- s.d.) AUC(0,infinity) standardized to a dose of 1 mg was 223 +/- 57 nmol l(-1) h, mean elimination half-life was 1.7 +/- 0.7 h and the mean clearance was 157 +/- 46 ml min(-1). These parameters were virtually identical after subcutaneous administration which had a bioavailability (F(0,infinity)) of 102 +/- 35% (90% CI 82, 117%) and t(max) of 0.5 +/- 0.2 h. The mean bioavailability of nebulized M6G was 6 +/- 2% (90% CI 4, 7%) with a t(max) of 1.2 +/- 0.8 h. Following oral M6G two plasma M6G peaks were seen in 7 of the 10 subjects, the first with a t(max) of 3.1 (+/- 0.9) h. The second peak had a t(max) of 13.4 (+/-5.0) h, started approximately 4 h after dosing, and was associated with the detection of plasma M3G and morphine, suggesting that M6G was significantly hydrolysed in the gut to morphine, which was then glucuronidated following absorption. Although the overall mean bioavailability was 11 +/- 3% (90% CI 9, 12%), confining the analysis to data from the first peak suggested a bioavailability of directly absorbed M6G of only 4 +/- 4%. Apart from a characteristic dysphoria following intravenous and subcutaneous M6G, there was no significant toxicity.
With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.
吗啡-6-葡萄糖醛酸苷（M6G）是吗啡的活性代谢产物之一，作为一种具有明显更高治疗指数的强效阿片类镇痛药，已引起广泛关注。迄今为止，相关研究采用的是静脉给药途径，而这在癌症相关疼痛的治疗中通常是不可接受的。本研究旨在确定M6G三种替代给药途径的药代动力学、毒性及心肺效应。
10名健康志愿者参与了一项开放随机研究。受试者分别接受2mg静脉推注、20mg口服、2mg皮下注射及4mg雾化吸入的M6G。监测脉搏、血压、呼吸频率和峰值流速，并使用评分量表和视觉模拟量表记录主观毒性。
静脉注射M6G后，以1mg剂量标准化的平均（±标准差）AUC(0,∞)为223±57nmol·l⁻¹·h，平均消除半衰期为1.7±0.7h，平均清除率为157±46ml·min⁻¹。皮下给药后的这些参数基本相同，其生物利用度（F(0,∞)）为102±35%（90%置信区间82,117%），t(max)为0.5±0.2h。雾化吸入M6G的平均生物利用度为6±2%（90%置信区间4,7%），t(max)为1.2±0.8h。口服M6G后，10名受试者中有7人出现两个血浆M6G峰，第一个峰的t(max)为3.1（±0.9）h。第二个峰的t(max)为13.4（±5.0）h，在给药后约4小时开始出现，且与血浆M3G和吗啡的检测相关，这表明M6G在肠道中被显著水解为吗啡，然后在吸收后被葡萄糖醛酸化。尽管总体平均生物利用度为11±3%（90%置信区间9,12%），但仅对第一个峰的数据进行分析表明，直接吸收的M6G的生物利用度仅为4±4%。除静脉和皮下注射M6G后出现的特征性烦躁不安外，未观察到明显毒性。
鉴于本研究及既往研究报道的毒性极小，皮下输注M6G可能为晚期癌症疼痛提供临床上有用的镇痛效果。雾化吸入的M6G经肺部吸收不显著，若阿片类药物在肺部显示出局部作用，减轻呼吸困难的感觉，那么雾化给药可能会使全身效应降至最低。口服M6G的生物利用度较差，但在肠道中被显著水解为吗啡，随后在吸收后被葡萄糖醛酸化。这条迂回途径占口服给药后全身可利用的M6G的大部分。
