Intestinal absorption mechanisms of 2'-deoxy-2'-beta-fluoro-4'-azidocytidine, a cytidine analog for AIDS treatment, and its interaction with P-glycoprotein, multidrug resistance-associated protein 2 and breast cancer resistance protein.

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Liu Y, Liu B, Zhang Y, Peng Y, Huang C, Wang N, Jiang J, Wang Q, Chang J

Eur J Pharm Sci. 2017 Jul 15;105:150-158. doi: 10.1016/j.ejps.2017.05.009. Epub 2017 May 6.

PubMed ID

28487144 [ View in PubMed

]

Abstract

2'-Deoxy-2'-beta-fluoro-4'-azidocytidine (FNC), a cytidine analog, has attracted great interest because of its potent activity against wild-type and multidrug-resistant HIV. The purpose of current study was to investigate the absorption mechanisms of FNC in the small intestine, as well as the interactions between FNC and P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). The experiments were performed using Caco-2 cells and the rat small intestine. The uptake experiment indicated that FNC concentration, extracellular pH and the incubated temperature could influence the uptake of FNC in Caco-2 cells. NaN3, verapamil, probenecid, MK571 and GF120918 could significantly increase the FNC uptake in Caco-2 cells. The transport experiment showed that both the absorption and secretion of FNC were concentration dependent. The secretion of FNC was approximately 2-fold greater than the absorption. In the presence of verapamil, probenecid, MK571 or GF120918, the efflux ratio decreased by >50%. In everted rat intestine, the absorption of FNC also depended on its concentration and was not significantly different in the different segments of the small intestine. Real-time RT-PCR results indicated that the gene expressions of P-gp, MRP2 and BCRP were up-regulated after exposure to FNC. The reduction in accumulation of rhodamine 123 after treatment with FNC revealed its ability to up-regulate P-gp activity. In conclusion, FNC was completely absorbed by passive diffusion and active transport mechanisms. P-gp, MRP2 and BCRP could influence the absorption of FNC in the small intestine. FNC could modulate the gene expressions of P-gp, MRP2 and BCRP, and increase the activity of P-gp.

DrugBank Data that Cites this Article

Drugs

Azvudine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Azvudine	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Regulator	Details
Azvudine	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Regulator	Details
Azvudine	P-glycoprotein 1	Protein	Humans	Unknown	Activator Regulator	Details