Ruble Gaye R, Giardino Odessa Z, Fossceco Stewart L, Cosmatos Dennis, Knapp Richard J, Barlow Norman J
Sanofi-aventis, Bridgewater, NJ, USA.
J Am Assoc Lab Anim Sci. 2006 Jan;45(1):25-9.
Drug metabolism and pharmacokinetic (DMPK) studies are an important phase in drug discovery research. Compounds are administered via the intravascular or extravascular routes to animals to calculate various pharmacokinetic parameters. An important step in this process is dissolving the novel compound in a safe vehicle. This procedure is particularly challenging for compounds that must be administered intravenously, as the solution must be clear before injection. There are no published guidelines on which vehicles, or combination of vehicles, are acceptable in a particular species, nor are there published data on the effects these vehicles have on clinical chemistry or hematology parameters, particularly in dogs. In this study, 9 vehicles commonly used at sanofi-aventis USA (propylene glycol, polyethylene glycol 400, glycofurol, hydroxypropyl Beta-cyclodextrin, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylacetamide, ethyl alcohol, and saline) were tested for adverse clinical reactions (such as vomiting or diarrhea) and for their effect on hematology and clinical chemistry parameters. Each vehicle was administered to a group of 8 Beagles by slow intravenous infusion, and blood was collected prior to infusion and at 24 h and 7 d postinfusion. Of 8 dogs given propylene glycol, 2 developed mild gastrointestinal signs (vomitus, diarrhea) after their infusions. None of the vehicles tested induced significant hematology or serum clinical chemistry abnormalities, nor were significant clinical signs noted after administration. We conclude that at the dose, route, and manner described, all of the vehicles tested in this study are clinically safe to use and have no acute effects on hematology or serum chemistry parameters.
药物代谢与药代动力学（DMPK）研究是药物研发过程中的重要阶段。通过血管内或血管外途径给动物施用化合物，以计算各种药代动力学参数。这一过程中的一个重要步骤是将新型化合物溶解在安全的溶媒中。对于必须静脉给药的化合物来说，这一过程尤其具有挑战性，因为注射前溶液必须澄清。目前尚无已发表的指南说明在特定物种中哪种溶媒或溶媒组合是可接受的，也没有关于这些溶媒对临床化学或血液学参数影响的已发表数据，特别是在犬类中。在本研究中，对赛诺菲-安万特美国公司常用的9种溶媒（丙二醇、聚乙二醇400、甘油乙缩醛、羟丙基-β-环糊精、二甲基亚砜、N-甲基-2-吡咯烷酮、二甲基乙酰胺、乙醇和生理盐水）进行了不良反应（如呕吐或腹泻）及其对血液学和临床化学参数影响的测试。通过缓慢静脉输注将每种溶媒给予一组8只比格犬，并在输注前、输注后24小时和7天采集血液。在给予丙二醇的8只犬中，有2只在输注后出现轻度胃肠道症状（呕吐、腹泻）。所测试的溶媒均未引起显著的血液学或血清临床化学异常，给药后也未观察到明显的临床症状。我们得出结论，在所描述的剂量、途径和方式下，本研究中测试的所有溶媒在临床上使用都是安全的，并且对血液学或血清化学参数没有急性影响。
