Dong Liping, Liu Wenjuan, Zhao Xiaoyuan, Yu Feng, Xu Yungen, Su Mengxiang
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Pharmaceuticals (Basel). 2022 Jun 27;15(7):801. doi: 10.3390/ph15070801.
Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its biological activities, a novel limonin derivative-HY-071085-was synthesized by structural modification, and has exhibited strong anti-inflammatory and analgesic activity. In order to achieve a thorough understanding of the biological actions of HY-071085 in vivo, this study evaluated the pharmacokinetics and bioavailability of HY-071085 in rats and beagle dogs, and the distribution and excretion in rats. Using ultra-high-performance liquid chromatography-tandem mass spectrometry, the kinetic profiles of HY-071085 in the plasma of healthy rats and beagle dogs after a single gavage, repeated gavages and the intravenous injection of HY-071085 were studied. The tissue distribution (heart, liver, spleen, lung, kidney, gastric tissue, intestine, brain, skin, testis, ovary and womb) and excretion of HY-071085 were also studied. These results showed that HY-071085 has nonlinear dynamic characteristics in rat and beagle dog plasma. It was found that the plasma concentrations of HY-071085 in female rats were significantly higher than those in male rats after a single oral administration. There were gender differences in the kinetic behavior of HY-071085 in rats; however, there was no difference identified in dogs. HY-071085 was mainly eliminated as metabolites in rats, and was distributed in most of the tissues except the brain, with the highest content being in the gastric tissue and intestinal arease, followed by the liver, spleen, fat, lung, kidney, ovary and heart. The bioavailability of HY-071085 in male and female rats was 2.8% and 10.8%, respectively, and was about 13.1% in beagle dogs. The plasma protein binding rate of HY-071085 in rats, beagle dogs and humans ranged from 32.9% to 100%, with obvious species differences. In conclusion, our study provides useful information regarding the absorption, distribution and excretion of HY-071085, which will provide a good base for the study of the mechanism of its biological effects.
柠檬苦素是天然药物开发中的研究热点之一。然而，其在水中的低溶解度导致口服生物利用度较差，阻碍了对其作为候选化合物潜力的进一步研究。为了克服这一限制并增强其生物活性，通过结构修饰合成了一种新型柠檬苦素衍生物——HY - 071085，它表现出较强的抗炎和镇痛活性。为了全面了解HY - 071085在体内的生物学作用，本研究评估了HY - 071085在大鼠和比格犬体内的药代动力学和生物利用度，以及在大鼠体内的分布和排泄情况。采用超高效液相色谱 - 串联质谱法，研究了单次灌胃、多次灌胃以及静脉注射HY - 071085后，健康大鼠和比格犬血浆中HY - 071085的动力学特征。还研究了HY - 071085的组织分布（心脏、肝脏、脾脏、肺、肾脏、胃组织、肠道、脑、皮肤、睾丸、卵巢和子宫）和排泄情况。这些结果表明，HY - 071085在大鼠和比格犬血浆中具有非线性动力学特征。发现单次口服给药后，雌性大鼠血浆中HY - 071085的浓度显著高于雄性大鼠。HY - 071085在大鼠体内的动力学行为存在性别差异；然而，在犬类中未发现差异。HY - 071085在大鼠体内主要以代谢产物形式消除，分布于除脑以外的大多数组织中，含量最高的是胃组织和肠道区域，其次是肝脏、脾脏、脂肪、肺、肾脏、卵巢和心脏。HY - 071085在雄性和雌性大鼠体内的生物利用度分别为2.8%和10.8%，在比格犬体内约为13.1%。HY - 071085在大鼠、比格犬和人体内的血浆蛋白结合率在32.9%至100%之间，存在明显的种属差异。总之，我们的研究提供了关于HY - 071085吸收、分布和排泄的有用信息，这将为研究其生物学效应机制提供良好基础。
