Komura Hiroshi, Iwaki Masahiro
Department of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
J Pharm Sci. 2008 May;97(5):1775-800. doi: 10.1002/jps.21121.
Intestinal first-pass metabolism has a great impact on the bioavailability of CYP3A substrates in humans, and the in vivo impact has quantitatively been evaluated using CYP3A inhibitors or inducers. In vitro and in vivo preclinical investigations for intestinal metabolism are essential in clarifying pharmacokinetic behavior in animal species and predicting the effect of intestinal metabolism in the human. In this review, we will discuss species differences in intestinal CYP3A enzymes, and CYP3A-mdediated intestinal elimination. Identical CYP3A4 enzyme is expressed in human intestine and liver, but different CYP3A enzymes in both tissues of the mouse and rat are found, that is, respective intestinal enzyme is considered as cyp3a13 and CYP3A62. There is little information on CYP3A enzymes in the monkey and dog intestine, unlike the liver. In vitro metabolic activities of midazolam and nisoldipine are higher in the human and monkey than in the rat. In vivo assessment of cyclosporine, midazolam, nifedipine, tacrolimus, and verapamil has been reported in various species (monkey, rat, mouse, and/or dog) including the human. For midazolam, the monkey shows significant in vivo intestinal metabolism, as evidenced in the human. The monkey might be an appropriate animal model for evaluating small intestinal first-pass metabolism of CYP3A substrates.
肠道首过代谢对人类CYP3A底物的生物利用度有很大影响，体内影响已通过使用CYP3A抑制剂或诱导剂进行了定量评估。进行肠道代谢的体外和体内临床前研究对于阐明动物物种的药代动力学行为以及预测人类肠道代谢的影响至关重要。在本综述中，我们将讨论肠道CYP3A酶的物种差异以及CYP3A介导的肠道消除。人类肠道和肝脏中表达相同的CYP3A4酶，但在小鼠和大鼠的这两种组织中发现了不同的CYP3A酶，也就是说，各自的肠道酶被认为是cyp3a13和CYP3A62。与肝脏不同，关于猴和犬肠道中CYP3A酶的信息很少。咪达唑仑和尼索地平的体外代谢活性在人和猴中高于大鼠。环孢素、咪达唑仑、硝苯地平、他克莫司和维拉帕米在包括人类在内的各种物种（猴、大鼠、小鼠和/或犬）中的体内评估已有报道。对于咪达唑仑，猴显示出显著的体内肠道代谢，正如在人类中所证实的那样。猴可能是评估CYP3A底物小肠首过代谢的合适动物模型。
