THE METABOLISM AND KINETICS OF DOXAZOSIN IN MAN, MOUSE, RAT AND DOG
THE METABOLISM AND KINETICS OF DOXAZOSIN IN MAN, MOUSE, RAT AND DOG
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DOI：
10.1111/j.1365-2125.1986.tb02849.x
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发表时间：
1986-01-01
影响因子：
3.4
通讯作者：
REID, JL
中科院分区：
文献类型：
--
作者：
KAYE, B;CUSSANS, NJ;REID, JL
用~(14)C标记化合物研究了多沙唑嗪在人、小鼠、大鼠和狗体内的代谢行为。使用一种特定的H.P.L.C.对非标记药物进行了生物利用度和药代动力学研究。方法。在口服和静脉给药后，所有研究物种的主要清除与药物有关的化合物的途径都是通过粪便。比较口服和静脉注射的数据表明，多沙唑嗪在人、小鼠和大鼠体内完全吸收，在狗体内有较好的吸收。这种药物被广泛代谢，例如，只有大约5%的剂量在人体内没有变化地被排泄。人体内的代谢主要包括6-和7-O-去甲基化以及6‘和7’-羟化。这些和一些次要的产物对老鼠、老鼠或狗和人来说是常见的。所有研究物种的血浆蛋白结合率都很高，从大鼠的95.3%到人类患者的98.3%不等。狗的口服生物利用度为60%，大鼠的口服生物利用度约为50%，这与报告的治疗剂量下人的63%的值相似。平均血浆清除值分别为13mlmin-1 kg-1(犬)、30mlmin-1 kg-1(大鼠)和1.2mlmin-1 kg-1(人)。狗的平均血浆半衰期为5h，大鼠的平均半衰期为1.2h：报告的人类志愿者的半衰期为9h。2.5h为哌唑嗪)。多沙唑嗪较长的血浆半衰期为每日一次给药提供了基础。
The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C‐labelled compound. Bioavailability and pharmacokinetic studies were also conducted with nonlabelled drug, using a specific h.p.l.c. method. Following both oral and intravenous administration, the major route of elimination of drug‐related compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog. The drug is extensively metabolized, e.g. only about 5% of the dose was excreted unchanged in man. Metabolism in man mainly involves 6‐ and 7‐ O‐demethylation and 6′ and 7′‐hydroxylation. These and some minor products were common to the mouse, rat or dog and man. Plasma protein binding was high in all species studied, ranging from 95.3% in the rat to 98.3% in human patients. Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63% reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min‐1 kg‐1 (dogs), 30 ml min‐1 kg‐1 (rats) and 1.2 ml min‐1 kg‐1 (human subjects). Mean plasma half‐life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half‐life of doxazosin provides the basis for once‐daily dosing.