Bronner U, Brun R, Doua F, Ericsson O, Burri C, Keiser J, Miézan T W, Boa Y F, Rombo L, Gustafsson L L
Division of Clinical Pharmacology, Karolinska Institute, Huddinge, Sweden.
Trop Med Int Health. 1998 Nov;3(11):913-7. doi: 10.1046/j.1365-3156.1998.00327.x.
With the use of a specific high-performance liquid chromatography (HPLC) method and a bioassay which determines trypanocidal activity, concentrations of melarsoprol were assessed in plasma, urine and cerebrospinal fluid (CSF) from 8 patients with late-stage Trypanosoma gambiense sleeping sickness. The aim was to unravel to what extent the bioassay codetermines biologically active metabolites of melarsoprol.
Subjects were given one dose of melarsoprol i.v. per day for 4 days (1.2, 2.4, 3.0-3.6, 3.0-3.6 mg per kg b.w., respectively). Plasma samples were obtained before the first melarsoprol injection, immediately after and at 1 h, 24 h and 5 days after the 4th injection. Urine was collected before melarsoprol therapy and at 24 h after the 4th injection. CSF samples were taken once before treatment and at 24 h after the 4th injection.
HPLC analyses showed that plasma concentrations immediately after the 4th injection varied from 2200 to 15,900 nmol/l; dropping to 0-1800 nmol/l at 1 h; and to undetectable levels at 24 h. In urine small amounts of melarsoprol were recovered. Melarsoprol could not be detected in CSF by HPLC. Immediately after injection, bioassay analyses showed plasma concentrations of the same magnitude as HPLC assays but at 1 h they were 4-65-fold higher than the levels assessed by HPLC. Even 24 h and 5 days after the 4th injection there was significant but decreasing activity. Urine levels were 40-260-fold higher than the measured HPLC concentrations, whereas there was low but detectable activity in CSF.
Results indicate that melarsoprol is rapidly eliminated from plasma. The significant trypanocidal activity determined by bioassay and simultaneous low or undetectable levels of melarsoprol assayed by HPLC indicate that the compound is transformed into metabolites with parasiticidal activity.
采用特定的高效液相色谱（HPLC）方法和一种测定杀锥虫活性的生物测定法，对8例晚期冈比亚锥虫昏睡病患者的血浆、尿液和脑脊液（CSF）中的美拉胂醇浓度进行评估。目的是弄清楚生物测定法在多大程度上共同决定了美拉胂醇的生物活性代谢物。
受试者每天静脉注射一剂美拉胂醇，共4天（分别为每千克体重1.2、2.4、3.0 - 3.6、3.0 - 3.6毫克）。在首次注射美拉胂醇前、首次注射后立即以及第4次注射后1小时、24小时和5天采集血浆样本。在美拉胂醇治疗前和第4次注射后24小时收集尿液。在治疗前和第4次注射后24小时采集一次脑脊液样本。
HPLC分析表明，第4次注射后即刻血浆浓度在2200至15900纳摩尔/升之间；1小时时降至0至1800纳摩尔/升；24小时时降至检测不到的水平。在尿液中回收了少量美拉胂醇。通过HPLC在脑脊液中检测不到美拉胂醇。注射后即刻，生物测定分析显示血浆浓度与HPLC测定结果相当，但1小时时比HPLC评估的水平高4至65倍。即使在第4次注射后24小时和5天仍有显著但逐渐降低的活性。尿液水平比HPLC测定浓度高40至260倍，而脑脊液中有低但可检测到的活性。
结果表明美拉胂醇从血浆中迅速消除。生物测定法测定的显著杀锥虫活性以及HPLC测定的同时低水平或检测不到的美拉胂醇表明该化合物转化为具有杀寄生虫活性的代谢物。
