title: Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence.
abstract: Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and anti-hypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant male-predominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.
authors.affiliation: Technology Laboratory Center, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.|School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
authors.forename: Chunming
authors.initials: C
authors.lastname: Lyu
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Rehabilitation, Changzheng Hospital Affiliated to Second Military Medicine University, Shanghai, 200003, People's Republic of China.
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Kou
authors.affiliation: Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. wei_hai@hotmail.com.
authors.forename: Hai
authors.initials: H
authors.lastname: Wei
authors.affiliation: Technology Laboratory Center, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. ningzh18@126.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People's Republic of China. joanzuo@cuhk.edu.hk.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000959:Antihypertensive Agents; D014704:Veratrum Alkaloids; C009649:veratramine
keywords: 7-hydroxyl-veratramine; enterohepatic recirculation; gender-dependent pharmacokinetics; veratramine; veratramine-3-O-sulfate