Study on biopharmaceutics classification and oral bioavailability of a novel multikinase inhibitor NCE for cancer therapy.
Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻⁴ mg·min⁻¹·cm⁻². The P(eff) value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. yyde2013@163.com.
Yang
Y
Yang
West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China. fanchunmeiok@163.com.
Chun-Mei
CM
Fan
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. hexuan9014@163.com.
Xuan
X
He
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA. renkemallee@gmail.com.
Ke
K
Ren
West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China. ymyzjk@163.com.
Jin-Kun
JK
Zhang
West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China. heyingju@tom.com.
Ying-Ju
YJ
He
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. luodyu@163.com.
Luo-Ting
LT
Yu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. zhengyu_iris@163.com.
Ying-Lan
YL
Zhao
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. chygong14@yahoo.com.cn.
Chang-Yang
CY
Gong
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. zhengyu_iris@163.com.
Yu
Y
Zheng
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. songxr@scu.edu.cn.
Xiang-Rong
XR
Song
Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. junzengscu@163.com.
Jun
J
Zeng
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001702:Biopharmaceutics; D004285:Dogs; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D047428:Protein Kinase Inhibitors