Comparison of pharmacokinetic and metabolic profiling among gossypol, apogossypol and apogossypol hexaacetate
Comparison of pharmacokinetic and metabolic profiling among gossypol, apogossypol and apogossypol hexaacetate
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DOI：
10.1007/s00280-007-0446-3
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发表时间：
2008-01-01
影响因子：
3
通讯作者：
Reed, John C.
中科院分区：
文献类型：
--
作者：
Jia, Lee;Coward, Lori C.;Reed, John C.
目的研究棉酚类似物、阿朴棉酚和阿朴棉酚六乙酸酯的稳定性、药动学和代谢，为同类产品的比较提供依据。使用液相色谱-质谱法定量测定这些类似物的代谢和药代动力学曲线结果在不同种属的血浆中，阿朴棉酚和棉酚的稳定性相似，但有20-40%的阿朴棉酚六乙酸酯转化为阿朴棉酚，同时生成相应的二乙酸酯、三乙酸酯、四乙酸酯和五乙酸酯。（+/-）-棉酚和（-）-棉酚在小鼠经口和静脉给药后显示出相当的药代动力学特征和口服生物利用度（12.2-17.6%），但清除率和V（ss）存在一些变化。在相同的摩尔剂量下，阿朴棉酚给药后显示出延迟的T（max）（1 h）、较慢的清除率和较少的分布。给药后，在小鼠血浆中容易观察到阿朴棉酚的单葡糖苷酸和二葡糖苷酸结合物。在芝麻油中配制的阿朴棉酚似乎具有更大的AUC，因此比在Cremophor EL：乙醇：盐水中配制的阿朴棉酚具有更高的口服生物利用度。相比之下，静脉注射阿朴棉酚六乙酸酯显示出最高的清除率，部分原因是其转化为阿朴棉酚。伴随着apogossypol hexaacetate（iv）的消失，apogossypol hexaacetate转化的apogossypol被定量检测到，约占血浆apogossypol hexaacetate总量的30%。口服阿朴棉酚六乙酸酯没有生物利用度，血浆中几乎没有阿朴棉酚。在人和小鼠肝微粒体中，除棉酚葡萄糖醛酸化外，很容易鉴别出阿朴棉酚及其乙酸酯的葡萄糖醛酸结合物。阿朴棉酚在人和小鼠肝微粒体制剂中比棉酚和阿朴棉酚六乙酸酯更稳定。结论阿朴棉酚和棉酚具有相似的口服和静脉药代动力学特征和体外稳定性，但阿朴棉酚似乎具有较慢的清除率，较大的AUC，和更好的微粒体稳定性。阿朴棉酚六乙酸酯在体外和体内环境中都转化为阿朴棉酚，并且缺乏任何可量化的口服生物利用度。
Purpose To characterize the stability, pharmacokinetics and metabolism of analogs of gossypol, apogossypol and apogossypol hexaacetate to provide a basis for comparison.Methods Gossypol, apogossypol and apogossypol hexaacetate were incubated in plasma or liver microsomes from various species, or administered to mice, respectively, from which the stability, metabolism and pharmacokinetic profiles of these analogs were quantitatively determined using a liquid chromatography-mass spectrometry (LC/MS/MS) method.Results In various species of plasma, apogossypol and gossypol exhibited similar stability, while 20-40% of apogossypol hexaacetate was converted into apogossypol with concurrent formation of the corresponding di-, tri-, tetra-, and penta-acetates of apogossypol. (+/-)-Gossypol and (-)-gossypol showed comparable pharmacokinetic profile and oral bioavailability (12.2-17.6%) with some variations of clearance and V (ss) following oral and intravenous administration to mice. At the same molar dose, apogossypol showed delayed T (max)(1 h), a slower clearance rate and less distribution after administration to mice. Mono- and di-glucuronide conjugates of apogossypol were readily observed in mouse plasma following administration. Apogossypol formulated in sesame oil appeared to possess larger AUC and thus higher oral bioavailability than that formulated in cremophor EL:ethanol:saline. In contrast, intravenous apogossypol hexaacetate exhibited highest clearance rate partially due to its conversion into apogossypol. Concomitant with disappearance of apogossypol hexaacetate (iv), apogossypol converted from apogossypol hexaacetate was quantitatively detected, and accounted for similar to 30% of total plasma apogossypol hexaacetate. Oral apogossypol hexaacetate showed no bioavailability with little apogossypol occurring in the plasma. In human and mouse liver microsomes, glucuronide conjugates of apogossypol and its acetates were readily identified with the exception of gossypol glucuronidation. Apogossypol appeared more stable in human and mouse liver microsomal preparations than gossypol and apogossypol hexaacetate.Conclusions Apogossypol and gossypol show similar oral and intravenous pharmacokinetic profiles and in vitro stability although apogossypol appears to have a slower clearance rate, larger AUC, and better microsomal stability. Apogossypol hexaacetate converts to apogossypol in both in vitro and in vivo settings and lacks any quantifiable oral bioavailability.