title: Pharmacokinetics of brucine after intravenous and oral administration to rats.
abstract: The toxicity depending on both dose and administration route is the major obstacle to the development of brucine, a bioactive alkaloid from Semen Strychni. In this study, the apparent partition coefficient and plasma protein binding extent of brucine were determined. In addition, the dose-dependency of the pharmacokinetics of brucine was investigated. Three intravenous (2.5, 5 and 10 mg/kg) and three oral (10, 20 and 40 mg/kg) doses were administered to rats. After intravenous administration, the systemic clearance was reduced and AUC was nonlinearly increased as a function of dose. Upon oral administration, brucine was rapidly absorbed (T(max)<0.5h), which was consistent with previously reported high Caco-2 P(app) values. The increase in AUC was proportional to the increase in dose. The oral bioavailability (F) did not vary with the dose (F=40.31%, 47.15% and 43.02% for 10, 20, 40 mg/kg doses, respectively). However, the dose-proportionality was not observed with C(max). The values of C(max)/Dose were calculated to be 92.92±45.83, 55.73±24.01 and 36.29±22.44 μg/L for 10, 20 and 40 mg/kg, respectively. The results of dose-dependent pharmacokinetic behavior under different administration routes may account for the significantly different toxicities of brucine between intravenous and oral administration.
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Han-Lu
authors.initials: HL
authors.lastname: Xiao
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Zhi-Peng
authors.initials: ZP
authors.lastname: Chen
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.forename: Tu-Lin
authors.initials: TL
authors.lastname: Lu
authors.forename: Yun
authors.initials: Y
authors.lastname: Fang
authors.forename: Bao-Chang
authors.initials: BC
authors.lastname: Cai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D010936:Plant Extracts / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012639:Seeds; D013331:Strychnine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D031451:Strychnos / Q000737:chemistry* / Q000633:toxicity
chemical_list: D010936:Plant Extracts; C083806:brucine; D013331:Strychnine