The Pharmacokinetics and Tissue Distribution of Harmine Derivative H-2-104 in Rats

Objective: Harmine (HM) is the main alkaloid of Peganum harmala L., which has antitumor, insecticide, and anti-inflammatory effects. However, it has limited use in clinical practice, due to potential high neurotoxicity. Therefore, the structure of HM was modified, to obtain H-2-104, which is a derivative with low neurotoxicity and reported benefit in the treatment of cystic echinococcosis (CE). This study explored the pharmacokinetic profile and tissue distribution of H-2-104. Methods: Plasma was collected from healthy rats at various time points following oral (20, 40, 80 mg/kg) and intravenous (i.v.; 1, 2, 4 mg/kg) administration of H-2-104. After the oral administration, tissues were collected at different time points and treated with acetonitrile precipitation. Using tinidazole as an internal standard, the concentration of H-2-104 in plasma and the distribution concentration in tissues were determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Then, multiple methods were used to evaluate the linear kinetics of H-2-104. Pharmacokinetic parameters were obtained using the 3P97 pharmacokinetic software. Results: The pharmacokinetics of H-2-104 in rats after oral and i.v. administration demonstrated linear kinetic characteristics, consistent with the two-compartment model. H-2-104 was rapidly absorbed but slowly metabolized after oral administration. After i.v. administration, H-2-104 rapidly spread and was quickly metabolized. The absolute oral bioavailability was 52.20%. Conclusions: The UPLC-MS/MS method established in this study was sensitive, efficient and reliable and could be used for the pharmacokinetics and tissue distribution study of H-2-104. This study provided a scientific basis for evaluating the druggability of HM derivatives and could be used as a reference for structural modification and dosage form design.