Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization

doi:10.1021/acs.cgd.8b01911

	Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization
	Li, Zhen 1,2; Li, Meiqi 2,3; Peng, Bo 2; Zhu, Bingqing 2; Wang, Jian-rong 2; Mei, Xuefeng 2
刊名	CRYSTAL GROWTH & DESIGN
	2019-03-01
卷号	19 期号:3 页码:1942-1953
ISSN号	1528-7483
DOI	10.1021/acs.cgd.8b01911
通讯作者	Mei, Xuefeng(xuefengmei@simm.ac.cn)
英文摘要	Diethylstilbestrol (DES), a synthetic non-steroidal estrogen, has been prescribed for advanced breast cancer and prostate cancer. However, its poor compliance, reactive metabolite toxicity and hydrophobicity-induced drug accumulation has limited its applications. In this study, we aimed to modulate its dissolution rate and reduce reactive metabolites and drug accumulation through cocrystallization. Cocrystals of DES with isonicotinamide (INA), picolinamide (PIN), nicotinamide (NIA), urea (UREA), sarcosine (SAR), and flavone (FLA) were obtained. Different crystallization strategies result in cocrystal polymorphs for DES with INA and FLA. Intrinsic dissolution rate (IDR) characterizations in pH 2.0 buffer solution were conducted. Two assumptions (enhancing C-max or prolonging T-max) with the aim of improving compliance were put forward. On the basis of the IDR results (DES-NIA with a 1.5-fold increase in IDR and DES-2FLA-B with a 5.5-fold decrease in IDR) and the pharmacological activities of coformers (NIA and FLA with CYPs inhibition and UGTs stimulation effects), the pharmacokinetic behaviors of these two cocrystals were further researched. The 2-fold prolongation of T-max in the PK profile DES-2FLA-B facilitated an improvement in compliance. In addition, the higher clearance rates and the potential to reduce oxidative metabolites in DES-2FLA-B help to decrease the drug accumulation and reduce the adverse effects of DES.
资助项目	Shanghai Natural Science Foundation[18ZR1447900] ; Youth Innovation Promotion Association CAS[2016257] ; CAS Key Technology Talent Program ; SANOFI-SIBS Scholarship
WOS关键词	PHARMACEUTICAL COCRYSTALS ; CRYSTAL ; ENZYMES ; SOLUBILITY ; FLAVONOIDS ; CHEMISTRY ; SALTS ; GELS
WOS研究方向	Chemistry ; Crystallography ; Materials Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000460996600057
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290310]
专题	中国科学院上海药物研究所
通讯作者	Mei, Xuefeng
作者单位	1.Nanchang Univ, Coll Pharm, Nanchang 330006, Jiangxi, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Pharmaceut Analyt & Solid State Chem Res Ctr, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Li, Zhen,Li, Meiqi,Peng, Bo,et al. Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization[J]. CRYSTAL GROWTH & DESIGN,2019,19(3):1942-1953.
APA	Li, Zhen,Li, Meiqi,Peng, Bo,Zhu, Bingqing,Wang, Jian-rong,&Mei, Xuefeng.(2019).Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization.CRYSTAL GROWTH & DESIGN,19(3),1942-1953.
MLA	Li, Zhen,et al."Improving Compliance and Decreasing Drug Accumulation of Diethylstilbestrol through Cocrystallization".CRYSTAL GROWTH & DESIGN 19.3(2019):1942-1953.