A Treatment Duration – Dependent Trend Toward <i>Gnaphalium affine</i> Extract and Febuxostat Interactions for Treating Hyperuricemic Nephropathy: From Antagonism to Addition

Background: Anti-hyperuricemic and nephroprotective efficacy of Gnaphalium affine has been demonstrated in in vitro and animal models. However, its effects on transporters mediating efflux or excretion of uremic toxins and upstream receptors or mediators of renal fibrosis remain understudied or unknown. Febuxostat (FX) is a first-line drug for urate-lowering therapy. As a more frequency of combination use of herb and conventional drug, potential interaction is therefore a legitimate concern.Purpose: (i) To investigate the effects of G. affine extract (GAD) on organic anion transporters 1/3 (OAT1/3), ATP-binding cassette transporter G2 (ABCG2), epidermal growth factor receptor (EGFR) and transforming growth factor-β1 (TGF-β1). (ii) To investigate the pharmacological and the pharmacokinetic (PK) interactions between GAD and FX.Study design and methods: This study combined network pharmacology-based approach and a hyperuricemic nephropathy (HN) rat model for target prediction, validation and efficacy evaluation. UHPLC-MS/MS methods for simultaneous determination of multiple components in plasma were applied for GAD and FX PK study.Results: GAD up-regulated liver Abcg2 and down-regulated kidney EGFR expressions to exert its hypouricemic and reno-protective activities. Co-treatment of GAD with FX resulted in a changing hypouricemic effect from antagonism to ‘no interaction’ and then to addition as the treatment duration prolongs. This phenomenon was also confirmed by PK results, which was characterized by an initial decrease followed by a prolonged weakening decrease or even an increase in GAD or FX exposure.Conclusions: These findings might provide support for clinical studies of the potential interactions between FX and herbal preparations from G. affine.