Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Integrated Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
PLoS One. 2021 Oct 20;16(10):e0258579. doi: 10.1371/journal.pone.0258579. eCollection 2021.
Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD3 deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib's area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.
维生素 D3（VD3）诱导肠道 CYP3A，代谢口服给予的抗白血病化疗药物地塞米松（DEX）和达沙替尼，可能导致维生素-药物相互作用。为了确定 VD3 状态对这些化疗药物的全身暴露和疗效的影响，我们使用 VD3 充足和缺乏的小鼠进行了药代动力学和抗白血病疗效研究。与 VD3 充足的小鼠相比，雌性 C57BL/6J 和 hCYP3A4 转基因 VD3 缺乏的小鼠十二指肠（但非肝脏）中的小鼠 Cyp3a11 和 hCYP3A4 表达显著降低，而缺乏的小鼠十二指肠中 Mdr1a、Bcrp 和 Mrp4 的表达显著升高。当比较连续口服 DEX 方案（类似于用于治疗儿科急性淋巴细胞白血病患者的方案）后 VD3 状态对 DEX 全身暴露的影响时，雄性 VD3 缺乏的小鼠在第 3.5 天的平均血浆 DEX 水平（31.7 nM）明显高于充足的小鼠（12.43 nM），但在其他任何时间点都没有。单次口服 DEX 后，VD3 缺乏的小鼠与充足的小鼠相比，DEX 全身暴露的统计学上有显著下降，但实际上没有差异。虽然 VD3 状态对口服达沙替尼的血浆药物浓度-时间曲线下面积没有影响，但 VD3 缺乏的雄性小鼠在 t = 0.25 小时的达沙替尼血浆水平明显更高。地塞米松不能逆转 BCR-ABL 白血病中 VD3 充足的小鼠与缺乏的小鼠的生存率较差。总之，尽管 VD3 水平显著改变了雌性小鼠的肠道小鼠 Cyp3a，但在雄性小鼠中，口服给予的 DEX 和达沙替尼的 DEX 血浆暴露仅在短暂时间内有所不同。同样，VD3 缺乏对单次口服 DEX 清除率的影响较小，表明 VD3 水平对 DEX 全身暴露的临床意义可能有限。
