Pharmacokinetic studies of a novel multikinase inhibitor for treating cancer by HPLC-UV.
Small-molecule inhibitors are promising antitumor drugs. We have designed and synthesized a novel multi-targeted inhibitor, 2-methylcarbamoyl-4-{4-[3-(trifluoro-methyl)benzamido]phenoxy}pyridinium (SKLB610), that potently inhibits human tumor growth. In the study, the pharmacokinetic profile of SKLB610 was investigated. A simple, rapid and sensitive high-performance liquid chromatography-ultraviolet detection method was developed for the determination of SKLB610 in rat plasma. Samples were extracted with methanol and SKLB610 was separated on a C18 column using a mobile phase system consisting of 55% acetonitrile and 45% water, with ultraviolet detection at 270 nm. Sorafenib was used as the internal standard. The retention times of SKLB610 and the internal standard were 5.6 and 8.1 min, respectively. The quantification limit was 67 ng/mL. The calibration curves were linear over a concentration range of 0.1-50 µg/mL. The inter-day and intra-day accuracy and precision were within ± 10%. The recovery and stability of the assay were evaluated from spiked rat plasma. The method was successfully applied to a pharmacokinetic study of SKLB610 in rats. The pharmacokinetic profile of SKLB610 indicated that the oral formulations should be further optimized to improve bioavailability and intravenous formulation of SKLB610 should be developed.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041 Sichuan, China.
Xun
X
Luo
Shuangzhi
S
Li
Yongmei
Y
Xie
Jun
J
He
Junming
J
Li
Hongjun
H
Lin
Ningyu
N
Wang
Shengyong
S
Yang
Yinglan
Y
Zhao
Luoting
L
Yu
Xiangrong
X
Song
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004355:Drug Stability; D016018:Least-Squares Analysis; D008297:Male; D011726:Pyridinium Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D011726:Pyridinium Compounds