Design, Synthesis, Characterization, Computational Study and Evalution of Some Novel Pyrazol-3-one Derivatives as Anti-inflammatory Agents

The study aimed to investigate the modulatory effects of Atractylodes lancea (Thunb.) DC. (A. lancea: AL), a promising candidate for treating cholangiocarcinoma, on cytochrome P450 (CYP450) 1A2 AND 3A1, pharmacokinetics and biodistribution in animals. Herbal medicine is becoming increasingly used to enhance general health and well-being, and it is also used alone for specific health problems or with modern medicine. To investigate CYP1A2 and CYP3A1 modulatory activities following long-term exposure, rats of both genders received oral doses of the formulated AL at 1,000 (low dose), 3,000 (medium dose), and 5,000 (high dose) mg/kg body weight daily for 12 months. For short-term effects, male rats were orally administered the formulated AL at 5,000 mg/kg body weight daily for 1, 7, 14 and 21 days. The pharmacokinetic study was conducted in male rats after administration of the formulated AL at the dose of 5,000 mg/kg body weight daily for nine months. Due to the poor solubility of ATD, which might affect the bioavailability of the compound, the bioavailability and biodistribution of the polylactic-co-glycolic acid nanoparticles of ATD (ATD-PLGA-NPs) were investigated in mouse liver using matrix-assisted laser desorption ionization-imaging mass spectrometer (MALDI-IMS). The biodistribution study was conducted in a male mouse receiving ATD-PLGA-NPs at the equivalent dose to ATD of 100 mg/kg body weight. The high dose of formulated AL produced an inducing effect on CYP1A2 but an inhibitory effect on CYP3A1 activities in male rats. The low dose, however, did not inhibit or induce the activities of both enzymes in male and female rats. The current investigation of CYP450 modulatory activities was part of a large study to evaluate chronic toxicity (long-term exposure) and to identify the metabolic pathway (short-term exposure) of the formulated AL. ATD reached a maximum plasma concentration (Cmax) of 359.73 ng/mL at 3 h (tmax). Mean residence time (MRT) and terminal phase elimination half-life (t1/2z) were 3.03 and 0.56 h, respectively. The extent of biodistribution of ATD in mouse livers receiving ATD-PLGA-NPs was 5-fold of that receiving free ATD. In order to prevent potential herb-drug interactions after prolonged use, clinical use of low-dose AL should be taken into consideration. ATD-PLGA-NPs is a possible drug delivery system for the treatment of cholangiocarcinoma.