Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure.
Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure.
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DOI：
10.1111/j.1476-5381.2011.01310.x
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发表时间：
2011-07
影响因子：
7.3
通讯作者：
Kang MH
中科院分区：
文献类型：
--
作者：
Cooper JP;Hwang K;Singh H;Wang D;Reynolds CP;Curley RW Jr;Williams SC;Maurer BJ;Kang MH
在一项II期临床试验中，芬维A胺[N-（4-羟基苯基）维A酰胺（4-HPR）]的高血浆水平与结局改善相关。4-HPR的低生物利用度限制了其治疗应用。本研究描述了4-HPR在人和小鼠中的代谢特征，并探讨了酮康唑（一种CYP 3A 4抑制剂）作为调节剂对增加小鼠中4-HPR血浆水平和增加4-HPR低生物利用度的影响。4-通过质谱分析鉴别HPR代谢物，并通过高效液相色谱法（HPLC）定量4-HPR及其代谢物[N-（4-甲氧基苯基）视黄酰胺（4-MPR）和4-氧代-N-（4-羟基苯基）视黄酰胺（4-氧代-4-HPR）]的水平。在合并的人和合并的小鼠肝微粒体以及人细胞色素P450（CYP）3A 4同工酶微粒体中进行酶活性和酶抑制剂效应的动力学分析。4-HPR在小鼠体内代谢受到抑制。在患者和小鼠的血浆中鉴定出6种4-HPR代谢物。4-HPR至少部分通过人CYP 3A 4氧化为4-氧代-4-HPR。CYP 3A 4抑制剂酮康唑可显著降低人和小鼠肝微粒体中4-氧代-4-HPR的形成。在两个品系的小鼠中，与单独的4-HPR相比，体内共施用酮康唑与4-HPR显著增加了4-HPR血浆浓度>两倍，并且还增加了4-氧代-4-HPR水平。小鼠可作为人4-HPR药代动力学的体内模型。体内数据表明，正常临床剂量的酮康唑与4-HPR联合给药可能会增加人体对4-HPR的全身暴露。
High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR. 4-HPR metabolites were identified by mass spectrometric analysis and levels of 4-HPR and its metabolites [N-(4-methoxyphenyl)retinamide (4-MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR)] were quantified by high-performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes. In vivo metabolism of 4-HPR was inhibited in mice. Six 4-HPR metabolites were identified in the plasma of patients and mice. 4-HPR was oxidized to 4-oxo-4-HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4-oxo-4-HPR formation in both human and mouse liver microsomes. In two strains of mice, co-administration of ketoconazole with 4-HPR in vivo significantly increased 4-HPR plasma concentrations by > twofold over 4-HPR alone and also increased 4-oxo-4-HPR levels. Mice may serve as an in vivo model of human 4-HPR pharmacokinetics. In vivo data suggest that the co-administration of ketoconazole at normal clinical doses with 4-HPR may increase systemic exposure to 4-HPR in humans.
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影响因子：
12.8
作者：
Ozpolat, B;Mehta, K;Lopez-Berestein, G
通讯作者：
Lopez-Berestein, G
影响因子：
11.4
作者：
O'Donnell, PH;Guo, WX;Maurer, BJ
通讯作者：
Maurer, BJ
影响因子：
7.3
作者：
Illingworth NA;Boddy AV;Daly AK;Veal GJ
通讯作者：
Veal GJ
影响因子：
16
作者：
Cheng, EHYA;Wei, MC;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
6.5
作者：
Chithalen, JV;Luu, L;Jones, G
通讯作者：
Jones, G