Lee Su-Jin, Joo Seul-A, Kim Heejeong, Lee Yunjong, Chung Suk-Jae, Chae Yoon-Jee, Maeng Han-Joo
College of Pharmacy, Gachon University, Incheon 21936, Korea.
Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Eur J Pharm Sci. 2023 Apr 1;183:106396. doi: 10.1016/j.ejps.2023.106396. Epub 2023 Jan 31.
Altered drug concentrations may induce unexpected toxicity or treatment failure; thus, understanding the factors that alter the pharmacokinetic profiles of drugs is crucial for optimal disease treatment. Vitamin D receptor (VDR), a nuclear receptor, regulates the expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1), which are crucial determinants of drug pharmacokinetics. In this study, we investigated the effects of 1α,25-dihydroxyvitamin D [1,25(OH)D], a VDR ligand, on the metabolism, transport, and pharmacokinetics of indinavir, a dual substrate of CYP3A4 and MDR1. 1,25(OH)D treatment for three days upregulated the expression levels of CYP3A4 and MDR1 in Caco-2 cells and consequently led to an increase in the level of a metabolite formed via CYP3A4 (indinavir M6) and the efflux ratio of indinavir in transport study. The increase in the metabolic reaction was also confirmed through a metabolism assay performed using the lysate of 1,25(OH)D-treated Caco-2 cells. In the Ussing chamber study conducted with the rat intestine, 1,25(OH)D treatment did not alter the transport of indinavir into the basolateral side but increased indinavir M6 formation. Similarly, plasma levels of the metabolite increased in 1,25(OH)D-treated rats; however, systemic exposure to indinavir led to insignificant alterations. Considering the overlapping substrate specificities for CYP3A4 and MDR1 and their significant roles in drug pharmacokinetics, VDR may play an important role in drug interactions of CYP3A4 and MDR1 substrates for accessing more effective and safe disease treatments.
药物浓度的改变可能会引发意外的毒性反应或治疗失败；因此，了解改变药物药代动力学特征的因素对于优化疾病治疗至关重要。维生素D受体（VDR）作为一种核受体，可调节细胞色素P450 3A4（CYP3A4）和多药耐药蛋白1（MDR1）的表达，而这两者是药物药代动力学的关键决定因素。在本研究中，我们探究了VDR配体1α,25 - 二羟基维生素D [1,25(OH)D] 对茚地那韦（CYP3A4和MDR1的双重底物）的代谢、转运及药代动力学的影响。1,25(OH)D处理三天可上调Caco - 2细胞中CYP3A4和MDR1的表达水平，进而导致在转运研究中通过CYP3A4形成的一种代谢产物（茚地那韦M6）水平升高以及茚地那韦的外排率增加。通过使用经1,25(OH)D处理的Caco - 2细胞裂解物进行的代谢试验，也证实了代谢反应的增加。在用大鼠肠道进行的尤斯灌流室研究中，1,25(OH)D处理并未改变茚地那韦向基底外侧的转运，但增加了茚地那韦M6的形成。同样，在经1,25(OH)D处理的大鼠中，该代谢产物的血浆水平升高；然而，茚地那韦的全身暴露导致的变化不显著。鉴于CYP3A4和MDR1重叠的底物特异性及其在药物药代动力学中的重要作用，VDR可能在CYP3A4和MDR1底物的药物相互作用中发挥重要作用，以实现更有效和安全的疾病治疗。
