Wasan K M, Peteherych K D, Najafi S, Zamfir C, Pritchard P H
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
J Pharm Pharm Sci. 2001 Sep-Dec;4(3):207-16.
The purpose of this project was to 1) assess the disposition kinetics of [3H]-cholesterol following co-administration with a novel hydrophilic compound, FM-VP4, and 2) determine the pharmacokinetics, tissue distribution and excretion of [3H]FM-VP4 following single oral (150 mg/kg which includes 100 mCi of radiolabel) and intravenous (15 mg/kg which includes 10 mCi of radiolabel) doses.
Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six treatment groups (n=4/group). Groups received single oral doses of 25 mCi/ml [3H]cholesterol alone or with 5, 10, 20, 50 and 100 mg/kg FM-VP4 at 0700 h. Ten percent Intralipid was used to solubilize and co-administer [3H]-cholesterol and FM-VP4. LC-MS analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid. Thin layer chromatography was used to confirm that the majority of radioactivity measured in plasma was associated with either esterified or unesterified cholesterol. In a second study pharmacokinetics of [3H]FM-VP4 were studied following intravenous or orally gavaged doses (n=8). Tissues, urine and feces were also collected in FM-VP4 kinetics study to measure tissue distribution of radioactivity. Plasma [3H]-cholesterol and [3H]FM-VP4 were tested for radioactivity.
FM-VP4 co-administration significantly decreased [3H]-cholesterol AUC0-48h and Cmax, and increased CL/F and Vd/F of [3H]-cholesterol as compared to controls in a dose-dependent manner. Following oral administration of [3H]FM-VP4, the majority of radioactivity following was recovered in the feces and gastrointestinal (GI) tract. The compound exhibited an oral bioavailability of 6.5%. Following IV administration, a two-compartment pharmacokinetic model was observed and the majority of the radioactivity was recovered in the GI tract.
FM-VP4 reduces plasma concentration of [3H]-cholesterol in fasting rats. [3H]FM-VP4 has a very low oral bioavailability.
本项目的目的是：1）评估与一种新型亲水性化合物FM-VP4共同给药后[3H]-胆固醇的处置动力学，以及2）确定单次口服（150mg/kg，其中包括100mCi放射性标记物）和静脉注射（15mg/kg，其中包括10mCi放射性标记物）剂量后[3H]FM-VP4的药代动力学、组织分布和排泄情况。
成年雄性Sprague Dawley大鼠在禁食过夜（12 - 16小时）且手术后48小时，被分为六个治疗组（每组n = 4）。各小组于07:00时接受单剂量口服25mCi/ml的[3H]-胆固醇，单独给药或与5、10、20、50和100mg/kg的FM-VP4联合给药。使用10%的英脱利匹特来溶解并共同给予[3H]-胆固醇和FM-VP4。液相色谱 - 质谱分析证实10%英脱利匹特中胆固醇和植物甾醇含量极低。采用薄层色谱法确认血浆中测得的大部分放射性与酯化或未酯化胆固醇相关。在第二项研究中，研究了静脉注射或口服给药（n = 8）后[3H]FM-VP4的药代动力学。在FM-VP4动力学研究中还收集了组织、尿液和粪便，以测量放射性的组织分布。检测血浆中[3H]-胆固醇和[3H]FM-VP4的放射性。
与对照组相比，FM-VP4共同给药以剂量依赖性方式显著降低了[3H]-胆固醇的AUC0 - 48h和Cmax，并增加了[3H]-胆固醇的CL/F和Vd/F。口服[3H]FM-VP4后，大部分放射性随后在粪便和胃肠道中回收。该化合物的口服生物利用度为6.5%。静脉注射后，观察到二室药代动力学模型，大部分放射性在胃肠道中回收。
FM-VP4可降低禁食大鼠血浆中[3H]-胆固醇的浓度。[3H]FM-VP4的口服生物利用度非常低。
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