首页> 外文期刊>British Journal of Clinical Pharmacology >Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.
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Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects.

机译:评估健康男性受试者中maraviroc的吸收,代谢和绝对生物利用度。

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AIMS: Two studies were conducted to: (i) quantify the amount of drug-related radioactivity in blood, plasma, urine and faeces following a (14)C-labelled dose of maraviroc; and (ii) investigate the pharmacokinetics, safety and tolerability of intravenous (i.v.) maraviroc and determine the absolute bioavailability of oral maraviroc. Metabolite profiling was also conducted. Data from both of these studies were used to construct a mass-balance model for maraviroc. METHODS: Study 1 was an open-label study in three healthy male subjects. All subjects received a single 300-mg oral solution dose of (14)C-labelled maraviroc. Study 2 included two cohorts of subjects. Cohort 1 involved a double-blind (third party open), four-way crossover study where eight subjects received escalating i.v. doses of maraviroc (3, 10 and 30 mg) with placebo insertion. Cohort 2 involved an open, two-way crossover study where 12 subjects received 30 mg maraviroc by i.v. infusion and 100 mg maraviroc orally in random order. In study 1, blood samples and all urine and faeces were collected up to at least 120 h postdose. In study 2, blood samples were taken at intervals up to 48 h postdose. Urine was also collected up to 24 h postdose in cohort 1 only. RESULTS: After oral administration in study 1, maraviroc was rapidly absorbed with a plasma T(max) reached by 2 h postdose for all three subjects. The maximum concentrations of radioactivity also occurred within 2 h for all subjects. There was a higher amount of radioactivity in plasma than in blood (blood/plasma ratio approximately 0.6 for AUC(t) and C(max)). Unchanged maraviroc was the major circulating component in plasma, accounting for approximately 42% of the circulating radioactivity. Following a 300-mg (14)C-labelled maraviroc dose, means of 76.4% and 19.6% of radioactivity were recovered in the faeces and urine, respectively. The mean total recovery of dosed radioactivity was 96%, with the majority of radioactivity being recovered within 96 h postdose. Profiling of the urine and faeces showed similar and extensive metabolism in all subjects. Unchanged maraviroc was the major excreted component (33%). The major metabolic pathways were determined and involved oxidation and N-dealkylation. Intravenous doses of maraviroc (3-30 mg) were well tolerated in study 2, and drug exposure was approximately proportional to dose within the studied range. Approximately 23% of total clearance (44 l h(-1)) was accounted for by renal clearance (10.2 l h(-1)). Mean volume of distribution at steady state was 194 l. Absolute bioavailability of a 100-mg oral tablet dose, by comparison with a 30-mg i.v. dose, was calculated to be 23.1%. CONCLUSIONS: Maraviroc is rapidly absorbed and extensively metabolized, although unchanged maraviroc is the major circulating component in plasma and is the major excreted component after oral dosing. The pharmacokinetics of maraviroc after i.v. administration is approximately proportional over the dose range studied. Renal clearance contributes 23% of total clearance. The absolute bioavailability of 100 mg oral maraviroc is 23%.
机译:目的:进行了两项研究:(i)量化(14)C标记的maraviroc剂量后血液,血浆,尿液和粪便中与药物相关的放射性量; (ii)调查静脉(i.v.)maraviroc的药代动力学,安全性和耐受性,并确定口服maraviroc的绝对生物利用度。还进行了代谢物分析。这两项研究的数据都用于构建maraviroc的质量平衡模型。方法:研究1是一项针对3名健康男性受试者的开放标签研究。所有受试者均接受单剂量300 mg口服溶液的(14)C标记的maraviroc。研究2包括两组受试者。同类群组1涉及一项双盲(第三方开放),四向交叉研究,其中八名受试者接受了i.v.剂量的maraviroc(3、10和30 mg)并插入安慰剂。第2组涉及一项开放的双向交叉研究,其中12名受试者接受了i.v.接受的30 mg马拉维罗克治疗。随机输注和100毫克maraviroc口服。在研究1中,在给药后至少120小时内收集了血液样本以及所有尿液和粪便。在研究2中,在给药后长达48小时的间隔内采集血液样本。也仅在第1组中在给药后24小时内收集尿液。结果:在研究1中口服给药后,所有三名受试者的maraviroc在给药后2 h迅速被血浆T(max)吸收。所有受试者的最大放射性浓度也均在2小时内出现。血浆中的放射性比血液中的放射性高(AUC(t)和C(max)的血/血浆比约为0.6)。不变的maraviroc是血浆中的主要循环成分,约占循环放射性的42%。服用300 mg(14)C标记的maraviroc剂量后,粪便和尿液中分别回收了76.4%和19.6%的放射性。剂量放射性的平均总回收率为96%,大多数放射性在给药后96小时内恢复。在所有受试者中,尿液和粪便的概况分析显示相似且广泛的新陈代谢。不变的maraviroc是主要的排泄成分(33%)。确定了主要的代谢途径,涉及氧化和N-脱烷基。在研究2中,静脉注射的maraviroc(3-30 mg)耐受性良好,药物暴露与研究范围内的剂量大致成正比。肾清除率(10.2 l h(-1))占总清除率(44 l h(-1))的23%。稳态时的平均分配量为194 l。与30毫克静脉注射片剂相比,100毫克口服片剂剂量的绝对生物利用度。剂量计算为23.1%。结论:Maraviroc被快速吸收并广泛代谢,尽管不变的Maraviroc是血浆中主要的循环成分,也是口服给药后主要的排泄成分。马拉维罗静脉注射后的药代动力学在所研究的剂量范围内,给药大致成比例。肾脏清除率占总清除率的23%。 100 mg口服maraviroc的绝对生物利用度为23%。

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