小鼠局部缓释镇痛剂的药代动力学评估

Taylor Simmons, Gerry Hish, Tara L Martin, Patrick A Lester
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引用次数: 0

摘要

作为生物医学研究方案的一部分,小鼠经常要接受痛苦的程序和手术。丁丙诺啡是一种部分μ-阿片受体激动剂和κ受体拮抗剂,通常用于减轻此类手术带来的疼痛。由于其药代动力学特征,丁丙诺啡需要频繁给药,造成操作压力,从而影响动物福利和研究数据。最近,一种长效透皮丁丙诺啡制剂(LA-bup)被批准用于猫科动物,可提供长达 4 天的术后镇痛。在这项研究中,我们在选定的时间点给雄性和雌性 CD-1 小鼠注射 0.36 毫克或 18 μL 的局部剂量,研究了单次局部注射 LA-bup 的药代动力学特征。在给药后 0.25、0.5、1、1.5、2、4、8、24、48 和 72 小时(n = 3 只小鼠/时间点)对血浆丁丙诺啡浓度进行了评估,结果显示,给药后 1 至 24 小时内,丁丙诺啡浓度仍高于所谓的治疗阈值(1 纳克/毫升)。在 24 和 48 小时内每天重复给药,血浆浓度在 72 小时内均高于 1 毫微克/毫升,随着时间的推移,累积或最大浓度变化极小。通过测量与单次给药小鼠同笼的未给药小鼠的血浆丁丙诺啡浓度,评估了局部给药是否会无意中转移给同笼的未给药小鼠。雄性小鼠没有表现出通过梳理或相互作用转移药物的情况,但在 26 只未服药的雌性小鼠中,有 2 只小鼠的血浆中检测到了丁丙诺啡浓度,这表明同笼雌性小鼠交叉摄入药物的发生率相对较低。这项研究表明,LA-丁丙诺啡是一种很有前景的小鼠镇痛药,可根据手术模型或镇痛治疗持续时间的长短,采用量身定制的镇痛策略。
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Pharmacokinetic Evaluation of a Topical Extended-release Analgesic in Mice.

Mice often undergo painful procedures and surgeries as part of biomedical research protocols. Buprenorphine, a partial μ-opioid receptor agonist and κ receptor antagonist, is commonly used to alleviate the pain associated with such procedures. Due to its pharmacokinetic profile, buprenorphine requires frequent dosing, resulting in handling stress that can impact animal welfare and study data. A long-acting transdermal buprenorphine formulation (LA-bup) was recently approved for use in cats to provide up to 4 d of postoperative analgesia. In this study, we characterized the pharmacokinetics of a single topical dosing of LA-bup in male and female CD-1 mice administered a 0.36-mg or 18-μL topical dose at select time points. Plasma buprenorphine concentrations were evaluated at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 48, and 72 h (n = 3 mice/time point) and remained above the purported therapeutic threshold (1 ng/mL) from 1 to 24 h postadministration. Repeated daily dosing at 24 and 48 h demonstrated plasma levels above 1 ng/mL for up to 72 h with minimal accumulation or changes in maximal concentrations over time. Inadvertent transfer of the topical drug to nondosed mice in the same cage was evaluated by measuring plasma buprenorphine concentrations in nondosed mice cohoused with a single-dosed mouse. Male mice did not demonstrate transfer of drug via grooming or interactions, yet 2 out of 26 nondosed female mice had detectable buprenorphine plasma levels indicating a relatively low incidence of cross-ingestion in cohoused female mice. This study demonstrates that LA-bup is a promising analgesic in mice that could be used for tailored analgesia strategies, depending on the surgical model or duration of analgesic therapy.

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American Society of Laboratory Animal Practitioners Position Statement: Handling and Physical Restraint of Research Animals. American Society of Laboratory Animal Practitioners Position Statement: Definition of Animal Welfare. Effect of Novel High-fat Diet Feeding Methods on Food Wastage, Weight Gain, Hair Coat Grease Accumulation, and Scratching Behavior in C57BL/6NCrl Mice. Identification and Treatment of Fur Mites (Radfordia lemnina) in California Deer Mice (Peromyscus californicus) Using Selamectin. American Society of Laboratory Animal Practitioners Position Statement: Animal Care Principles.
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