Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.
Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.
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发表时间：
1997-12
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通讯作者：
M. Paine;M. Khalighi;J. Fisher;D. Shen;K. Kunze;C. Marsh;J. Perkins;K. Thummel
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作者：
M. Paine;M. Khalighi;J. Fisher;D. Shen;K. Kunze;C. Marsh;J. Perkins;K. Thummel
细胞色素P450 3A（CYP 3A）代谢多种临床重要药物。对于其中的一些（例如，环孢素、维拉帕米、咪达唑仑），肠粘膜中的CYP 3A有助于其广泛和可变的首过提取。为了进一步表征这种现象，我们测量了20个人供体肠的十二指肠、空肠和回肠部分分离的粘膜中CYP 3A含量和对探针底物咪达唑仑的催化活性。为了进行比较，对20个人类供体肝脏进行了相同的测量，其中8个肝脏与8个肠道来自相同的供体。三个肠道区域的匀浆和微粒体CYP 3A含量之间存在良好的相关性。中位微粒体CYP 3A含量在十二指肠中最高，在回肠中最低（31 pmol/mg蛋白vs. 17 pmol/mg蛋白）。关于咪达唑仑1 '-羟基化动力学，各肠区的中位Km与中位肝脏Km相似，约为4 μ M。相反，从肝脏到十二指肠到空肠到回肠，中位Vmax降低（850 vs. 644 vs. 426 vs. 68 pmol/min/mg）。肠道区域的固有清除率（Vmax/Km）遵循相似的趋势;十二指肠固有清除率中位数与肝脏固有清除率相当（分别为157和200 μ l/min/mg）。Vmax与除回肠外的所有组织的CYP 3A含量相关。供体间十二指肠和空肠Vmax和CYP 3A含量变化>30倍。还分析了从6条肠的每隔1英尺切片制备的微粒体的CYP 3A以及两种辅酶。总的来说，从十二指肠到空肠中段，CYP 3A活性、CYP 3A含量和CYP 3A还原酶活性略有上升，然后下降到空肠远端和回肠。细胞色素b5含量和细胞色素b5还原酶活性在整个肠道变化不大。空肠的局部内源性咪达唑仑1 '-羟基化清除率最高，其次是十二指肠和回肠（分别为144、50和19 ml/min）。总的来说，这些结果表明，小肠上段作为肠道CYP 3A介导的首过代谢的主要部位，并为某些CYP 3A底物的口服生物利用度的个体间差异提供了依据。
Cytochrome P450 3A (CYP3A) metabolizes a diverse array of clinically important drugs. For some of these (e.g., cyclosporine, verapamil, midazolam), CYP3A in the intestinal mucosa contributes to their extensive and variable first-pass extraction. To further characterize this phenomenon, we measured CYP3A content and catalytic activity toward the probe substrate midazolam in mucosa isolated from duodenal, jejunal and ileal sections of 20 human donor intestines. For comparison, the same measurements were performed for 20 human donor livers, eight of which were obtained from the same donors as eight of the intestines. Excellent correlations existed between homogenate and microsomal CYP3A content for the three intestinal regions. Median microsomal CYP3A content was greatest in the duodenum and lowest in the ileum (31 vs. 17 pmol/mg of protein). With respect to midazolam 1'-hydroxylation kinetics, the median Km for each intestinal region was similar to the median hepatic Km, approximately 4 microM. In contrast, the median Vmax decreased from liver to duodenum to jejunum to ileum (850 vs. 644 vs. 426 vs. 68 pmol/min/mg). Intrinsic clearance (Vmax/Km) followed a similar trend for the intestinal regions; median duodenal intrinsic clearance was comparable to hepatic intrinsic clearance (157 and 200 microl/min/mg, respectively). Vmax correlated with CYP3A content for all tissues except the ileum. Duodenal and jejunal Vmax and CYP3A content varied by >30-fold among donors. Microsomes prepared from every other 1-foot section of six intestines were also analyzed for CYP3A as well as for two coenzymes. In general, CYP3A activity, CYP3A content and CYP reductase activity rose slightly from duodenum to middle jejunum and then declined to distal jejunum and ileum. Cytochrome b5 content and cytochrome b5 reductase activity varied little throughout the intestinal tract. Regional intrinsic midazolam 1'-hydroxylation clearance was greatest for the jejunum, followed by the duodenum and ileum (144, 50 and 19 ml/min, respectively). Collectively, these results demonstrate that the upper small intestine serves as the major site for intestinal CYP3A-mediated first-pass metabolism and provides a rationale for interindividual differences in oral bioavailability for some CYP3A substrates.