Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts
Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts
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DOI：
10.1016/s0009-9236(03)00199-1
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发表时间：
2003-10-01
影响因子：
6.7
通讯作者：
Fattinger, K
中科院分区：
文献类型：
--
作者：
Girardin, F;Rentsch, KM;Fattinger, K
背景：在一些国家，目前正在评估二乙酰吗啡的医疗处方作为严重依赖麻醉成瘾者的治疗选择。由于静脉受损，许多病人肌肉注射或口服二乙酰吗啡。因此，我们描述了在高剂量范围内肌肉注射和口服二乙酰吗啡通常需要麻醉成瘾者的药代动力学。方法：对8例海洛因依赖患者分别给予2乙酰吗啡肌注、3口服、1静脉注射剂量和氘标记吗啡（吗啡- n-甲基-d3[吗啡-d3]）口服和静脉注射试验剂量。采用液相色谱-质谱法测定二乙酰吗啡、单乙酰吗啡、吗啡、吗啡-3-葡糖苷、吗啡-6-葡糖苷、吗啡-d3的动脉血浆浓度。结果：肌内注射二乙酰吗啡（小于或等于200-250 mg）表现出二乙酰吗啡、单乙酰吗啡和吗啡的线性动力学，并导致持续的二乙酰吗啡暴露（生物利用度，380% +/- 157%[平均+/- SD]），与静脉给药相比，单乙酰吗啡和吗啡浓度的峰值更低和延迟。口服二乙酰吗啡（小于或等于600毫克）产生的全身二乙酰吗啡和单乙酰吗啡暴露可以忽略不计，但与线性动力学和吗啡的高生物利用度（67% +/- 19%）、吗啡-3-葡糖苷（205% +/- 52%）和吗啡-6-葡糖苷（180% +/- 61%）相关。此外，口服二乙酰吗啡比同时服用吗啡-d3吸收更快、程度更大。结论：基于二乙酰吗啡的线性药代动力学、高生物利用度以及口服二乙酰吗啡对吗啡的快速和持久吸收，推荐肌注和口服途径作为二乙酰吗啡医用处方安全可行的替代途径。
Background: In several countries medical prescription of diacetylmorphine is currently being evaluated as atreatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramuscular and oral diacetylmorphine in the high dose range usually required in narcotic addicts.Methods: Three intramuscular doses, 3 oral doses, and 1 intravenous dose of diacetylmorphine and oral and intravenous test doses of deuterium-labeled morphine (morphine-N-methyl-d3 [morphine-d3]) were administered to 8 heroin-addicted patients. Arterial plasma concentrations of diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6-glucuronide, and morphine-d3 were measured by liquid chromatography mass spectrometry.Results: Intramuscularly administered diacetylmorphine (less than or equal to200-250 mg) exhibited linear diacetylmorphine, monoacetylmorphine, and morphine kinetics and resulted in sustained diacetylmorphine exposures (bioavailability, 380% +/- 157% [mean +/- SD]) and in lower and delayed peak monoacetylmorphine and morphine concentrations as compared with intravenous administration. Oral diacetylmorphine (less than or equal to600 mg) yielded negligible systemic diacetylmorphine and monoacetylmorphine exposures but was associated with linear kinetics and high bioavailabilities for morphine (67% +/- 19%), morphine-3-glucuronide (205% +/- 52%), and morphine-6-glucuronide (180% +/- 61%). In addition, oral diacetylmorphine was absorbed more rapidly and to a greater extent than a concomitant test dose of morphine-d3.Conclusions: On the basis of the linear pharmacokinetics, the high bioavailability of intramuscular diacetylmorphine, and the rapid and extended morphine absorption from oral diacetylmorphine, the intramuscular and oral routes can be recommended as safe and feasible alternatives to the intravenous route for medical prescription of diacetylmorphine.