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首页> 美国卫生研究院文献>Frontiers in Pharmacology >Pharmacokinetics and Metabolism of Cyadox and Its Main Metabolites in Beagle Dogs Following Oral Intramuscular and Intravenous Administration
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Pharmacokinetics and Metabolism of Cyadox and Its Main Metabolites in Beagle Dogs Following Oral Intramuscular and Intravenous Administration

机译：口服肌内和静脉内给药后比格犬及其主要代谢产物Cyadox及其主要代谢产物的药代动力学和代谢

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摘要

Cyadox (Cyx) is an antibacterial drug of the quinoxaline group that exerts markedly lower toxicity in animals, compared to its congeners. Here, the pharmacokinetics and metabolism of Cyx after oral (PO), intramuscular (IM), and intravenous (IV) routes of administration were studied to establish safety criteria for the clinical use of Cyx in animals. Six beagle dogs (3 males, 3 females) were administered Cyx through PO (40 mg kg−1 b.w.), IM (10 mg kg−1 b.w.), and IV (10 mg kg−1 b.w.) routes with a washout period of 2 weeks in a crossover design. Highly sensitive high-performance liquid chromatography with ultraviolet detection (HPLC-UV) was employed for determination of Cyx and its main metabolites, 1, 4-bisdesoxycyadox (Cy1), cyadox-1-monoxide (Cy2), N-(quinoxaline-2-methyl)-cyanide acetyl hydrazine (Cy4), and quinoxaline-2-carboxylic acid (Cy6) in plasma, urine and feces of dogs. The oral bioavailability of Cyx was 4.75%, suggesting first-pass effect in dogs. The concentration vs. time profile in plasma after PO administration indicates that Cyx is rapidly dissociated into its metabolites and eliminated from plasma earlier, compared to its metabolites. The areas under the curve (AUC) of Cyx after PO, IM and IV administration were 1.22 h × μg mL−1, 6.3 h × μg mL−1, and 6.66 h × μg mL−1, while mean resident times (MRT) were 7.32, 3.58 and 0.556 h, respectively. Total recovery of Cyx and its metabolites was >60% with each administration route. In feces, 48.83% drug was recovered after PO administration, while 18.15% and 17.11% after IM and IV injections, respectively, suggesting renal clearance as the major route of excretion with IM and IV administration and feces as the major route with PO delivery. Our comprehensive evaluation of Cyx has uncovered detailed information that should facilitate its judicious use in animals by improving understanding of its pharmacology.
机译：Cyadox（Cyx）是喹喔啉类的抗菌药物，与同类药物相比，对动物的毒性明显降低。在此，研究了口服（PO），肌肉内（IM）和静脉内（IV）给药途径后Cyx的药代动力学和代谢，以建立Cyx在动物中临床使用的安全标准。通过PO（40 mg kg -1 bw），IM（10 mg kg -1 bw）和六只比格犬（3只雄性，3只雌性）给予Cyx （10 mg kg -1 bw）路线在交叉设计中的淘汰期为2周。采用紫外检测的高效灵敏高效液相色谱法（HPLC-UV）测定Cyx及其主要代谢物1，4，4-双脱氧cyadox（Cy1），cyadox-1-一氧化碳（Cy2），N-（喹喔啉-2 -甲基）氰化物乙酰肼（Cy4）和喹喔啉-2-羧酸（Cy6）在狗的血浆，尿液和粪便中的含量。 Cyx的口服生物利用度为4.75％，表明在狗中具有首过效应。 PO给药后血浆中浓度与时间的关系曲线表明，与Cyx的代谢产物相比，Cyx迅速分解成其代谢产物，并较早地从血浆中清除。 PO，IM和IV给药后Cyx的曲线下面积（AUC）为1.22 h×μgmL -1 ，6.3 h×μgmL -1 和6.66 h×μgmL -1 ，而平均停留时间（MRT）分别为7.32、3.58和0.556 h。每种给药途径的Cyx及其代谢物的总回收率> 60％。在粪便中，PO给药后可回收48.83％的药物，而IM和IV注射后分别可回收18.15％和17.11％，这表明IM和IV给药时肾脏清除率是排泄的主要途径，粪便是PO递送的主要途径。我们对Cyx的综合评估发现了详细信息，这些信息应通过增进对Cyx药理学的理解来促进其在动物中的明智使用。

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