Ma Minglang, Zhang Yongxiang, Fang Yanjun, Lu Yixing, Huang Huiguo, Zeng Zhenling, Zeng Dongping
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety. Evaluation, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal. Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.
Front Pharmacol. 2024 Jul 30;15:1413872. doi: 10.3389/fphar.2024.1413872. eCollection 2024.
Cryptosporidiosis is considered a crucial zoonotic disease caused by widely distributing parasitic protozoa called spp. Nitazoxanide is the only FDA-approved drug but is only effective with a good immune response of the host. In addressing this unmet medical need, we previously identified a compound, namely, LN002, as a potent alternative oxidase inhibitor against cryptosporidiosis. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of LN002 in rats, rapid and sensitive high-performance liquid chromatography was developed and validated for the separation and detection of LN002 in plasma, tissue samples, and intestinal contents. In this study, a single dose of oral administration and intravenous injection of LN002 was used to determine the levels of LN002 in plasma, tissue samples, and intestinal contents by UHLC. Results of the study indicated that after intravenous administration of 1 mg/kg LN002, the AUC0-24 h, T,V, and Cl were 7024.86 h·ng/mL, 10.91 h, 1.69 L/kg, and 0.11 L/h/kg, respectively. After oral administration of a single dosage of 100, 200, and 400 mg/kg LN002, the T, C, AUC, T, F, V, and Cl/F in plasma of rats were 1 h, 849.88-4033.21 ng/mL, 2280.41-7498.10 h·ng/mL, 17.96-18.83 h, 0.27%-0.32%, 581.54-869.21 L/kg, and 25.97-39.00 L/h/kg, respectively. After oral administration of 200 mg/kg, LN002 was extensively distributed in the main tissues of rats, and massive amounts of LN002 were distributed in the intestine and intestinal contents, indicating its potential as an effective anti-Cryptosporidium compound. After oral administration of a single dosage of 200 mg/kg, LN002 has a low bioavailability and high levels in the intestine, which is crucial for the safe and effective treatment of cryptosporidiosis. Overall, the results of this study provide valuable data support for the future study of LN002.
隐孢子虫病被认为是一种由广泛分布的寄生虫原生动物隐孢子虫属引起的重要人畜共患病。硝唑尼特是唯一获得美国食品药品监督管理局（FDA）批准的药物，但仅在宿主具有良好免疫反应时才有效。为满足这一未被满足的医疗需求，我们之前鉴定出一种化合物，即LN002，作为一种针对隐孢子虫病的有效替代氧化酶抑制剂。为阐明LN002在大鼠体内的药代动力学、绝对生物利用度和组织分布，开发并验证了快速灵敏的高效液相色谱法，用于分离和检测血浆、组织样本及肠道内容物中的LN002。在本研究中，通过超高效液相色谱法（UHLC），采用单次口服给药和静脉注射LN002的方式，来测定血浆、组织样本及肠道内容物中LN002的含量。研究结果表明，静脉注射1mg/kg LN002后，药时曲线下面积（AUC0-24 h）、达峰时间（Tmax）、分布容积（Vd）和清除率（Cl）分别为7024.86 h·ng/mL、10.91 h、1.69 L/kg和0.11 L/h/kg。单次口服100、200和400mg/kg LN002后，大鼠血浆中的Tmax、峰浓度（Cmax）、AUC、T1/2、生物利用度（F）、Vd和清除率（Cl/F）分别为1h、849.88 - 4033.21 ng/mL、2280.41 - 7498.10 h·ng/mL、17.96 - 18.83 h（T1/2）、0.27% - 0.32%、581.54 - 869.21 L/kg和25.97 - 39.00 L/h/kg。口服200mg/kg后，LN002在大鼠的主要组织中广泛分布，且大量LN002分布于肠道和肠道内容物中，表明其作为一种有效的抗隐孢子虫化合物的潜力。单次口服200mg/kg后，LN002的生物利用度较低，但在肠道中的含量较高，这对于隐孢子虫病的安全有效治疗至关重要。总体而言，本研究结果为LN002的后续研究提供了有价值的数据支持。
