Comparative oral and intravenous pharmacokinetics of phlorizin in rats having type 2 diabetes and in normal rats based on phase II metabolism

Abstract

Phlorizin (PHZ), a type of dihydrochalcone widely found in Rosaceae such as apples, is the first compound discovered as a sodium-glucose cotransporter (SGLT) inhibitor.

Phlorizin ameliorates obesity-associated endotoxemia and insulin resistance in high-fat diet-fed mice by targeting the gut microbiota and intestinal barrier integrity

“…Previous works have demonstrated a critical role of PHZ in preventing and treating MDs by directly decreasing the blood glucose level via competitive inhibition of SGLT2; 35,36 however, the extremely low bioavailability of PHZ casted doubt on whether this was the only mechanism behind the therapeutic effect. 10 Thus, the current work hypothesized that the gut microbiota was an alternative target responsible for the observed beneficial effects of PHZ intake. This work applied a high-throughput sequencing technology to systematically analyze changes in the fecal microbiota composition after PHZ supplementation.…”

“…8,9 However, despite the fact that SGLT2 is regarded as a new class of therapeutic targets for managing MDs, 8,9 currently only few PHZ-based products are designed and available for such purpose mainly due to the extremely low bioavailability of PHZ. 9,10 Indeed, a large amount of ingested but unabsorbed PHZ will reach the gastrointestinal tract, and some of which will be hydrolyzed to PHT. 11 Gastrointestinal disorders induced by high-fat diet (HFD) are associated with MDs, including abnormal blood glucose metabolism, elevated triglycerides, and decreased high-density lipoproteins, contributing to the development of obesity, T2DM, and cardiovascular disease.…”

Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

“…These data demonstrating the effect of SGLT inhibition or ablation to reverse systemic glucose toxicity refocused attention on their clinical development. Phlorizin's potential for clinical use was limited by its effects to reduce glucose uptake in brain (30) -whether by inhibition of SGLTs (31,32) or SGLT-like channels (33) -as well as by its poor oral bioavailability (34)(35)(36). To address these limitations, investigators developed inhibitors specific to SGLT2, the expression of which is confined to the kidney (37).…”

Dietary natural flavonoids treating cancer by targeting aryl hydrocarbon receptor

“…After absorption with or without metabolic conjugation, flavonoids are transported to target organs where they exert their anticarcinogenic activity. The molecular mechanisms of the anticarcinogenic effects of flavonoids include their antagonistic effect on the AhR, and regulation of phase I and II drug metabolizing enzymes and phase III transporters (Kawai 2018;Wang et al 2019). In addition, these anticancer effects may be partly due to the antioxidant properties of the flavonoids, and recent studies suggest that interactions with essential signal transduction pathways may be more important (Alaklabi et al 2018;Ojelabi et al 2018).…”