Department of Chemistry and Biochemistry, Laurentian University, 935 Ramsey Lake Rd, Sudbury, Ontario P3E 2C6, Canada.
Department of Forensic Science, Laurentian University, 935 Ramsey Lake Rd, Sudbury, Ontario P3E 2C6, Canada.
J Anal Toxicol. 2019 Oct 17;43(9):726-733. doi: 10.1093/jat/bkz074.
Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) analysis of dextromethorphan (DXM) and its metabolites-dextrorphan, 3-methoxymorphinan (3-MEM) and 3-hydroxymorphinan-in skeletal remains of rats exposed to DXM under different dosing patterns is described. Rats (n = 20) received DXM in one of four dosing patterns: acute (ACU1 or ACU2-100 or 200 mg/kg, i.p.; n = 5, respectively) or repeated (REP1 or REP2-3 doses of 25 or 50 mg/kg, i.p., 30 min apart; n = 5, respectively). Drug-free animals (n = 5) served as negative controls. Following euthanasia, the animals decomposed to skeleton outdoors. Bones were sorted by animal and skeletal element (vertebra, femur, pelvis, tibia, rib and skull), washed, air-dried and pulverized prior to dynamic methanolic drug extraction, filtration/pass-through extraction and analysis by UPLC-QToF-MS in positive electrospray ionization mode. Analyte levels (expressed as mass-normalized response ratios, RR/m) differed significantly between ACU1 and ACU2 (Mann-Whitney (MW), P < 0.05) in all skeletal elements for all analytes investigated, and between REP1 and REP2 in most skeletal elements for 3-MEM and 3-HOM, but in all skeletal elements for DXM. Between ACU1 and ACU2, and between REP1 and REP2, analyte level ratios (RRi/RRj) differed significantly (MW, P < 0.05) in 3/6 to 6/6 skeletal elements, depending on the ratios concerned, with no analyte level ratio differing significantly between both ACU1 vs ACU2 and REP1 vs REP2. Kruskal-Wallis (KW) analysis showed skeletal element to be a main effect for all analyte levels and analyte level ratios in all ACU and REP groups examined (P < 0.05). For data pooled only according to exposure pattern, KW analysis showed dose pattern to be a main effect for both analyte levels and analyte level ratios (P < 0.05). These data illustrate a dependence of these measures on dose, dose pattern and skeletal element, suggesting that some exposure patterns may be distinguished by toxicological analysis of bone.
超高效液相色谱-四极杆飞行时间质谱法（UPLC-QToF-MS）分析了在不同给药模式下暴露于右美沙芬（DXM）的大鼠骨骼中 DXM 及其代谢物右啡烷、3-甲氧基吗啡烷（3-MEM）和 3-羟吗啡烷的情况。大鼠（n=20）接受了以下四种给药模式之一的 DXM 处理：急性（ACU1 或 ACU2-100 或 200mg/kg，腹腔注射；分别为 n=5）或重复（REP1 或 REP2-3 剂量 25 或 50mg/kg，腹腔注射，间隔 30 分钟；分别为 n=5）。未用药的动物（n=5）作为阴性对照。安乐死后，动物在户外分解为骨骼。将骨骼按动物和骨骼元素（脊椎、股骨、骨盆、胫骨、肋骨和颅骨）分类，用甲醇动态提取，过滤/通过提取，然后用正电喷雾电离模式的 UPLC-QToF-MS 进行分析。在所有研究的分析物中，ACU1 和 ACU2 之间（Mann-Whitney（MW），P<0.05）在所有骨骼元素中，以及在 REP1 和 REP2 之间（MW，P<0.05）在大多数骨骼元素中，3-MEM 和 3-HOM 的分析物水平差异均有统计学意义，但在所有骨骼元素中 DXM 则存在差异。在 ACU1 和 ACU2 之间以及在 REP1 和 REP2 之间，根据所涉及的比值，分析物水平比值（RRi/RRj）在 3/6 到 6/6 骨骼元素之间存在显著差异（MW，P<0.05），但在 ACU1 与 ACU2 以及 REP1 与 REP2 之间，没有分析物水平比值存在显著差异。Kruskal-Wallis（KW）分析显示，骨骼元素是所有 ACU 和 REP 组中所有分析物水平和分析物水平比值的主要影响因素（P<0.05）。对于仅根据暴露模式进行数据汇总的情况，KW 分析显示剂量模式是分析物水平和分析物水平比值的主要影响因素（P<0.05）。这些数据表明，这些测量结果依赖于剂量、剂量模式和骨骼元素，表明某些暴露模式可能通过骨骼的毒理学分析来区分。
