Involvement of CYP3A4 and MDR1 in altered metabolism and transport of indinavir in 1,25(OH)2D3-treated Caco-2 cells

Abstract

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 D₃ [1,25(OH)₂D₃], a VDR ligand, on the metabolism, transport, and pharmacokinetics of indinavir, a dual substrate of CYP3A4 and MDR1. 1,25(OH)₂D₃ 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)₂D₃-treated Caco-2 cells. In the Ussing chamber study conducted with the rat intestine, 1,25(OH)₂D₃ 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)₂D₃-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.

Keywords: 1α,25-dihydroxyvitamin D3; Caco-2 cells; Cytochrome P450 3A4; Indinavir; Multidrug resistance protein 1; Vitamin D receptor.