Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan.
Department of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan; Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
J Infect Chemother. 2021 May;27(5):702-706. doi: 10.1016/j.jiac.2020.12.014. Epub 2020 Dec 30.
The novel nucleoside analog, 4'-cyano-2'-deoxyguanosine (CdG), possesses inhibitory activity against both the wild-type and resistant hepatitis B virus. Since the dosage of the currently available nucleoside analog preparations needs to be adjusted, depending on renal function, we investigated the effect of renal dysfunction on the pharmacokinetics of CdG in a rat model of chronic kidney disease (CKD).
CKD model rats were either intravenously or orally administered CdG at a dose of 1 mg/kg. The concentration of CdG in plasma, organs (liver and kidney) and urine samples were determined by means of a UPLC system interfaced with a TOF-MS system.
Following intravenous administration, the plasma retention of CdG was prolonged in CKD model rats compared to healthy rats. In addition, the clearance of CdG was well correlated with plasma creatinine levels in CKD model rats. Similar to the results for intravenous administration, the plasma concentration profiles of CdG after oral administration were also found to be much higher in CKD model rats than in healthy rats. However, the results for the organ distribution and urinary excretion of CdG, the profiles of which were similar to that of healthy rats, indicated that CdG did not accumulate to a significant extent in the body.
The extent of renal dysfunction has a direct influence on the pharmacokinetics (plasma retention) of CdG without a significant accumulation, indicating that the dosage of CdG will be dependent on the extent of renal function. .
新型核苷类似物 4'-氰基-2'-脱氧鸟苷（CdG）对野生型和耐药乙型肝炎病毒均具有抑制活性。由于目前可用的核苷类似物制剂的剂量需要根据肾功能进行调整，因此我们研究了肾功能障碍对慢性肾病（CKD）大鼠模型中 CdG 药代动力学的影响。
CKD 模型大鼠以 1mg/kg 的剂量静脉或口服给予 CdG。通过 UPLC 系统与 TOF-MS 系统联用的方法，测定血浆、器官（肝和肾）和尿液样品中 CdG 的浓度。
与健康大鼠相比，静脉给予 CdG 后，CKD 模型大鼠的血浆保留时间延长。此外，在 CKD 模型大鼠中，CdG 的清除率与血浆肌酐水平密切相关。与静脉给药的结果相似，口服给予 CdG 后，其在 CKD 模型大鼠中的血浆浓度曲线也明显高于健康大鼠。然而，CdG 的器官分布和尿排泄结果与健康大鼠相似，表明 CdG 没有明显的蓄积。
肾功能障碍的严重程度直接影响 CdG 的药代动力学（血浆保留），但不会导致明显的蓄积，这表明 CdG 的剂量将取决于肾功能的严重程度。
