de Vries E M, Lammers L A, Achterbergh R, Klümpen H-J, Mathot R A A, Boelen A, Romijn J A
Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
Department of Hospital Pharmacy, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
PLoS One. 2016 Jul 19;11(7):e0159552. doi: 10.1371/journal.pone.0159552. eCollection 2016.
Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR.
To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65).
Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole.
We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.
细胞色素P450酶介导的肝脏药物代谢会因患者的营养状况而改变。P450酶的表达部分受组成型雄烷受体（CAR）调控。禁食会调节P450酶和CAR的表达，并影响肝脏药物清除率。我们推测，禁食诱导的P450介导的药物清除率改变是由CAR介导的。
为了研究这一问题，我们使用了一种在人体中验证过的药物混合物，该混合物由五种广泛使用的药物组成，作为特定P450酶的探针：咖啡因（CYP1A2）、美托洛尔（CYP2D6）、奥美拉唑（CYP2C19）、咪达唑仑（CYP3A4）和S-华法林（CYP2C9）。将这种混合物给予野生型（WT，C57Bl/6）小鼠或CAR基因缺陷型（CAR-/-）小鼠，这些小鼠要么自由进食，要么禁食24小时。在预定的时间间隔采集血液样本，测量药物浓度以及同源/直系同源P450酶（Cyp1a2、Cyp2d22、Cyp3a11、Cyp2c37、Cyp2c38和Cyp2c65）的肝脏mRNA表达。
禁食使WT和CAR-/-小鼠的Cyp1a2和Cyp2d22表达降低，Cyp3a11和Cyp2c38表达增加。与WT小鼠相比，CAR-/-小鼠中Cyp1a2的降低幅度较小。与WT小鼠相比，CAR-/-小鼠的基础Cyp2c37表达较低。禁食降低了WT和CAR-/-小鼠中所有测试药物的清除率。在进食的小鼠中，缺乏CAR与奥美拉唑、美托洛尔和咪达唑仑清除率的降低有关。禁食诱导的S-华法林清除率降低在WT小鼠中比在CAR-/-小鼠中更大。在Cyp1a2-咖啡因和Cyp2c37-奥美拉唑的情况下，药物清除率的变化与特定P450酶的表达模式相关。
我们得出结论，CAR对几种由P450酶代谢的广泛使用药物的肝脏清除很重要。然而，禁食诱导的P450介导的药物清除率改变在很大程度上独立于CAR。
