The pharmacokinetics of JS-38, a novel antineoplastic drug, in rats

Summary

To evaluate the pre-clinical pharmacokinetics of JS-38(C₂₂H₁₄O₄N₂S₂F₆ MW: 548), a study was conducted in Wistar rats (3 ♀, 2 ♂: 200∼250 g about 6 or 7 months). The concentration-time curve of JS-38 in rats demonstrated the pharmacokinetic (PK) characteristics of a two-compartmental model. The area under the concentration-time curve from zero to infinity (AUC _0−∞) for the low, middle and high dosage (i.e. 20, 50 and 125 mg•kg⁻¹) amounted to 46.850±19.946, 161.101±58.877 and 312.565±187.273 mg/L•h respectively; a positive correlation was demonstrated between theAUC _0−∞ and the dosages in question (r=0.99). The average time to reach maximum concentration (T _max) was 3, (RSD: 20.4% and the half-life (t _1/2) was 11.4h (RSD: 8.8%P>0.05. For the low, middle and high dosage, the maximum concentration (C _max) was 4.882, 11.248, and 13.431μg•mL⁻¹ respectively. After the administration of JS-38, except for the brain and spinal marrow, the drug distribution in the different body tissues varied, in particular in the liver, intestine and thyroid gland. A significant distribution of JS-38 was detected in cancerous tissues, and its concentrations demonstrated a tendency increase over time. There was a certain degree of distribution in the bone marrow. The urine samples showed that JS-38 nearly was practically not eliminated in its original form. The amount eliminated after 72h via the bile was only 1.03±0.1% of the administered dose. In the rat model, most of the JS-38 in its original form (53.58±22.28%) was excreted via the feces. When the intragastric administration of doses of 20, 50 and 125 mg•kg⁻¹ was compared with i.v. administered JS-38 (1 mg•kg⁻¹), the absolute bioavailability amounted to 22.2±9.5% 30.4±14.5% and 23.6±11.3% respectively. It was found that this compound is well absorbed in to the system and that it shows favorable PK properties. The outcome of this early pre-clinical study indicates that JS-38 is a promising drug candidate for further development.