The pharmacokinetics of JS-38, a novel antineoplastic drug, in rats.
To evaluate the pre-clinical pharmacokinetics of JS-38(C22H1404N2S2F6, MW: 548), a study was conducted in Wistar rats (3 female, 2 male: 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-infinity)) for the low, middle and high dosage (i.e., 20, 50 and 125 mg x kg(-1)) amounted to 46.850 +/- 19.946, 161.101 +/- 58.877 and 312.565 +/- 187.273 mg/L x h respectively; a positive correlation was demonstrated between the AUC(0-infinity). and the dosages in question (r = 0.99). The average time to reach maximum concentration (Tmax) was 3.( RSD: 20.4% and the half-life (t(1/2)) was 11.4 h( RSD: 8.8% P > 0.05. For the low, middle and high dosage, the maximum concentration (Cmax) was 4.882, 11.248, and 13.431 microg x 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 x kg(-1) was compared with i.v. administered JS-38 (1 mg x 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.
Ng
Hong Zha
HZ
Tongji University, Tongji Hospital, Shanghai, People's Republic of China. hongzh97@yahoo.com.cn
Fang
Yu
Y
Li
Ying
Y
Fan
Ting-Ting
TT
Qin
Yan
Y
Liu
Quan-Hai
QH
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005243:Feces / Q000737:chemistry; D005260:Female; D006845:Hydrocarbons, Fluorinated / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D006845:Hydrocarbons, Fluorinated; C533647:JS-38 compound