Michaud Véronique, Simard Chantale, Turgeon Jacques
Drug Metab Lett. 2010 Apr;4(2):95-103. doi: 10.2174/187231210791292735.
Previous studies have indicated that CYP3As are involved in the metabolism of the prokinetic agent domperidone.The objectives of our study were to characterize further the role of specific CYP3A isoforms in the metabolism of domperidone and to compare the kinetic parameters of domperidone to those of the CYP3A probe drug midazolam. Intrinsic clearance for the formation of domperidone major metabolite (5-hydroxydomperidone) was the highest with rCYP3A4 (0.4 mL/min/nmol CYP450) compared to rCYP3A5 (0.04 mL/min/nmol CYP450). The addition of cytochrome b5 to recombinant enzymes (rCYP3A4 or rCYP3A5) increased up to 6-fold the Vmax for the formation of 5-hydroxydomperidone. In contrast, much similar intrinsic clearance values for rCYP3A4 and rCYP3A5 were determined in the respective formation of either 1-hydroxmidazolam (1.28 and 1.57 mL/min/nmol CYP450) or 4-hydroxymidazolam(0.04 and 0.06 mL/min/nmol CYP450). Vmax for the formation of midazolam metabolites was increased to a lesser extent(1.5-3-fold) by the addition of cytochrome b5. Ketoconazole more potently inhibited CYP3A4 than CYP3A5 for both domperidone and midazolam. However, the addition of cytochrome b5 to the incubation mixture appeared to decrease the inhibitory potency of ketoconazole towards CYP3A4 for domperidone but not for midazolam. Our results indicate that CYP3A4 plays major role in the metabolism of domperidone. We demonstrated a modulatory role of cytochrome b5mostly for the metabolism of domperidone and confirmed selective inhibition of CYP3A4 over CYP3A5 by ketoconazole. Comparison of domperidone kinetic parameters to those of the CYP3A probe drug midazolam suggests that domperidone exhibits a much higher CYP3A4/CYP3A5 selectivity ratio than midazolam.
先前的研究表明，细胞色素P450 3A（CYP3A）参与促胃肠动力药多潘立酮的代谢。我们研究的目的是进一步明确特定CYP3A亚型在多潘立酮代谢中的作用，并将多潘立酮的动力学参数与CYP3A探针药物咪达唑仑的动力学参数进行比较。与重组人CYP3A5（0.04 mL/分钟/纳摩尔CYP450）相比，重组人CYP3A4形成多潘立酮主要代谢物（5-羟基多潘立酮）的内在清除率最高（0.4 mL/分钟/纳摩尔CYP450）。向重组酶（重组人CYP3A4或重组人CYP3A5）中添加细胞色素b5可使5-羟基多潘立酮形成的Vmax增加高达6倍。相比之下，在形成1-羟基咪达唑仑（分别为1.28和1.57 mL/分钟/纳摩尔CYP450）或4-羟基咪达唑仑（分别为0.04和0.06 mL/分钟/纳摩尔CYP450）时，重组人CYP3A4和重组人CYP3A5的内在清除率值非常相似。添加细胞色素b5后，咪达唑仑代谢物形成的Vmax增加幅度较小（1.5至3倍）。酮康唑对多潘立酮和咪达唑仑的抑制作用，对CYP3A4的抑制作用比对CYP3A5更强。然而，向孵育混合物中添加细胞色素b5似乎会降低酮康唑对多潘立酮中CYP3A4的抑制效力，但对咪达唑仑则不然。我们的结果表明，CYP3A4在多潘立酮的代谢中起主要作用。我们证明了细胞色素b5主要对多潘立酮的代谢具有调节作用，并证实酮康唑对CYP3A4的抑制作用比对CYP3A5更具选择性。将多潘立酮的动力学参数与CYP3A探针药物咪达唑仑的动力学参数进行比较表明，多潘立酮的CYP3A4/CYP3A5选择性比率比咪达唑仑高得多。
