Yoon-Jee Chae

Flavonoids are widely consumed dietary polyphenols that modulate drug disposition via membrane transporters. Increasing attention has been paid to methoxyflavones (MeO-FLVs) because methoxylation can increase membrane permeability and metabolic stability, potentially elevating transporter-mediated drug–drug interaction risk; however, position-specific effects are poorly defined. We profiled a series of structurally related flavones (3-OH-FLV, 3-MeO-FLV, 5-MeO-FLV, 6-MeO-FLV, and 7-MeO-FLV) across major uptake and efflux transporters. In vitro uptake and bidirectional transport assays demonstrated that methoxyflavones inhibited renal organic anion transporters 1 and 3 (OAT1/OAT3), organic cation transporter 2 (OCT2), and efflux transporters P-glycoprotein (MDR1)/breast cancer resistance protein (BCRP) more potently than 3-OH-FLV, although the inhibitory potency varied depending on the methoxy substitution position, particularly for OAT1 and OCT2. Cytotoxicity reversal assays supported functional inhibition of MDR1 and BCRP by the methoxyflavones. In vivo interaction studies were performed for the selected methoxyflavones using metformin and furosemide as transporter-relevant probe drugs in rats. Metformin pharmacokinetics were measurably altered by 3-MeO-FLV and 7-MeO-FLV, consistent with transporter-related modulation of metformin disposition, potentially involving OCT2. For furosemide, a clear interaction was observed with 6-MeO-FLV and 7-MeO-FLV. Overall, these findings suggest that the methoxylation pattern influences transporter inhibition profiles and in vivo pharmacokinetic effects, although further studies with larger compound sets are needed to define structure–activity relationships and transporter selectivity.

Background/Objectives: Oral delivery of semaglutide (Rybelsus) relies on sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) to enhance peptide absorption. However, formulation constraints and SNAC’s localized gastric mechanism have prompted the exploration of alternative enhancers. This study evaluated whether sodium caprate (C10), a well-characterized medium-chain fatty acid (MCFA), could achieve systemic exposure comparable to SNAC-based formulations when co-formulated in an immediate-release (IR) tablet. Methods: Preformulation studies assessed the physicochemical properties and buffering capacity of C10. Mechanistic feasibility was evaluated through Caco-2 transport studies and rat pharmacokinetic (PK) trials using aqueous suspensions, comparing the concentration-dependent effects of C10 and SNAC. Based on these findings, three IR tablet architectures (monolayer, bilayer, and dry compression-coated) were developed. The optimized formulation was evaluated in beagle dogs (14 mg semaglutide) and compared with the SNAC-based reference product. Results: C10 exhibited sufficient buffering capacity to neutralize acidic environments. In Caco-2 and rat PK studies, C10 enhanced semaglutide absorption in a concentration-dependent manner, yielding exposure levels equivalent to SNAC at matched doses. Among the tablet designs, the monolayer tablet showed the highest dissolution similarity (f₂ = 67.8) to Rybelsus. In beagle dogs, the optimized monolayer formulation produced pharmacokinetic parameters, including C_max, AUC_last, and t_1/2, that overlapped with those of the SNAC-based reference drug product under matched dosing conditions. Conclusions: These results demonstrate that C10 can effectively support oral semaglutide delivery when incorporated into a rationally designed IR tablet. The findings support the feasibility of MCFA-based permeation enhancer platforms as formulation alternatives to SNAC for oral peptide therapeutics.

Background: Organic cation transporter 2 (OCT2) mediates the renal uptake of cisplatin and is a principal contributor to its dose-limiting nephrotoxicity. Despite reports of OCT2 inhibition by various phytochemicals, the structure–activity relationships (SARs) governing inhibition and their functional implications remain poorly understood. Methods: We systematically evaluated OCT2 inhibitory activity across a structurally diverse library of 146 phytochemicals, including anthraquinones, flavanols, stilbenes, and isoflavones, using Madin–Darby canine kidney (MDCK) cells stably overexpressing OCT2. Structure–activity relationships were analyzed using non-parametric statistics and multivariate logistic regression, and functional relevance was assessed via cisplatin-induced cytotoxicity assays. Results: Inhibitory activity varied widely across the library, with potent inhibitors identified across multiple chemical scaffolds. Non-parametric statistical analyses revealed no significant differences in overall activity distributions among scaffold classes. Notably, chemical substituent patterns, rather than core scaffold identity, were the primary drivers of OCT2 inhibitory potency. Methoxylation was consistently associated with enhanced OCT2 inhibition, particularly within isoflavones, although its impact varied across structural scaffolds. The selected OCT2 inhibitors markedly reduced cisplatin-mediated cell death in OCT2-expressing cells but not in mock-transfected controls, confirming an OCT2-dependent mechanism of protection. Conclusions: This study establishes a structure-guided framework linking phytochemical OCT2 inhibition to nephroprotective potential and identifies methoxylation as a major determinant of OCT2-targeted intervention strategies.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are widely used in type 2 diabetes and cardiometabolic diseases, and their pharmacokinetic characteristics generally confer a low risk of clinically relevant drug–drug interactions (DDIs). Most clinical studies demonstrate that these agents can be co-administered safely with commonly prescribed medications without dose adjustment, although strong enzyme inducers such as rifampin can reduce systemic exposure, and pharmacodynamic interactions may still arise. However, existing evidence is largely derived from short-term studies in healthy volunteers, with limited data in special populations and minimal evaluation of metabolite- or transporter-mediated interactions. This review summarizes the available in vitro and in vivo pharmacokinetic and DDI data for SGLT2 inhibitors, identifies key knowledge gaps related to polypharmacy, metabolite effects, and vulnerable patient groups, and outlines future research priorities to ensure their safe and effective use in real-world clinical practice.

This study presents the development and validation of a fluorescence-based high-performance liquid chromatography (HPLC) method for the quantification of alectinib in rat plasma, with a focus on the application of Analytical Quality by Design (AQbD) to bioanalytical method development. Unlike conventional QbD applications, which primarily address synthetic formulations or instrumental settings, this study systematically applied AQbD principles to the complex environment of biological matrices. Critical method parameters, including the organic phase ratio, buffer concentration, and flow rate, were identified through Failure Mode and Effects Analysis, and optimized using a Box–Behnken design. The final method exhibited excellent linearity (R² >0.99) over a concentration range of 5–1,000 ng/mL, with a lower limit of quantification of 5 ng/mL. It also showed high accuracy (95.6–102%), precision (relative standard deviation < 11%), and consistent recovery (98.3–105%), with minimal matrix effects. Alectinib stability was confirmed under various handling conditions. This method was successfully applied in a pharmacokinetic study after intravenous and oral administration of alectinib in rats. These results highlight the value of AQbD in addressing specific challenges of bioanalysis and demonstrate its utility in establishing a sensitive, robust, and regulatory-compliant method suitable for pharmacokinetic applications.

Breast cancer resistance protein (BCRP), a member of the ATP-binding cassette transporter family, plays a key role in the efflux of various drugs and is linked to multidrug resistance in cancer therapy. Flavonoids, particularly those with a flavonol backbone, have shown promise as inhibitors of BCRP activity; however, their specific inhibitory effects are not fully understood. This study explored the inhibitory effects of 77 flavonols on BCRP and identified 22 compounds with significant inhibitory activity. Among them, 14 flavonols had half-maximal inhibitory concentrations (IC₅₀) values below 5 µM, effectively reversing BCRP-mediated resistance to SN-38 in vitro. Molecular docking analysis revealed key interactions between flavonols and BCRP, including π-stacking, hydrogen bonding, and hydrophobic interactions. Structural modifications, including hydroxylation and methylation, enhanced the binding affinity of the flavonols. In vivo studies with 3,4′-dimethoxyflavone and 3,6,3′,4′-tetramethoxyflavone resulted in increased systemic exposure to sulfasalazine, a known BCRP substrate. These findings provide mechanistic insights into flavonol-BCRP interactions, suggesting their potential to enhance drug exposure and efficacy. Future research should focus on clinical applications to explore the therapeutic potential of these flavonols for improved drug responses.