Preclinical pharmacokinetics, CYP phenotyping, and tissue distribution study of novel anti-breast cancer candidate S-011-1559

被引：10

作者：

Verma, Sarvesh Kumar ^{[1
,2
]}

Biswas, Arpon ^{[1
,2
]}

Kumar, Mukesh ^{[1
,2
]}

Mishra, Anjali ^{[1
,3
]}

Choudhury, Abhijit Deb ^{[1
,2
]}

Agrawal, Sristi ^{[1
,3
]}

Sanap, Sachin Nashik ^{[1
,3
]}

Bisen, Amol Chhatrapati ^{[1
,3
]}

Sharma, Ashok Kumar ^{[4
]}

Panda, Gautam ^{[4
]}

Bhatta, Rabi Sankar ^{[1
]}

机构：

[1] CSIR Cent Drug Res Inst, Pharmaceut & Pharmacokinet Div, BS 10-1,Sect 10,Sitapur Rd, Lucknow 226031, Uttar Pradesh, India

[2] Jawaharlal Nehru Univ, New Delhi, India

[3] Acad Sci & Innovat Res AcSIR, Ghaziabad, India

[4] CSIR Cent Drug Res Inst, Div Med & Proc Chem, Lucknow, Uttar Pradesh, India

来源：

XENOBIOTICA | 2022年 / 52卷 / 05期

关键词：

S-011-1559; triple-negative breast cancer; HSA drug binding; CYP phenotyping; pharmacokinetics; tissue distribution; PLASMA-PROTEIN BINDING; DRUG; CHALLENGES; METABOLISM; DISCOVERY; AGENT;

D O I：

10.1080/00498254.2022.2101033

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

S-011-1559 is a tyrosine-derived novel benzoxazine CDRI molecule targeted to the oestrogen-related receptor (ER-alpha/beta) modulator in breast cancer. To explore the pharmacokinetics of S-011-1559, a selective and sensitive bioanalytical method using LC-MS/MS was established and validated in different biological matrices of female rats. Blood-to-plasma ratio and plasma protein binding (PPB) of S-011-1559 were found to be 97% in both rats and humans, respectively. The human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) binding was found in the range of > 68 to 45% and >14% respectively. Half-life and intrinsic clearance by microsomal stability study were found to be 28.83 min and 0.05 mL/min/mg in rats, 78.35 min and 0.036 mL/min/mg in humans, respectively. The IC50 value of S-011-1559 against CYP isoforms was revealed to moderately inhibit CYP2D6 by a reversible non-competitive mechanism. Tissue distribution of S-011-1559 on single intravenous injection at 2 mg/kg was found in the order of C lungs > C mammary gland > C spleen > C heart > C kidney > C liver > C brain. The data from the present study provides crucial information about S-011-1559 for further development as a novel potential drug candidate in modulating ER-alpha/beta receptors of lung and breast neoplasia.

引用

页码：476 / 487

页数：12

共 24 条

[1] Enantioselective inhibition of Cytochrome P450-mediated drug metabolism by a novel antithrombotic agent, S002-333: Major effect on CYP2B6 [J].