Transmembrane transport of metformin is highly controlled by transporters including organic cation transporters (OCTs), plasma membrane monoamine transporter (PMAT), and multidrug/toxin extrusions (MATEs). Hepatic OCT1, intestinal OCT3, renal OCT2 on tubule basolateral membrane, and MATE1/2-K on tubule apical membrane coordinately work to control metformin disposition. Drug–drug interactions (DDIs) of metformin occur when co-administrated with perpetrators via inhibiting OCTs or MATEs. We aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model characterizing interplay of OCTs and MATEs in the intestine, liver, and kidney to predict metformin DDIs with cimetidine, pyrimethamine, trimethoprim, ondansetron, rabeprazole, and verapamil. Simulations showed that co-administration of perpetrators increased plasma exposures to metformin, which were consistent with clinic observations. Sensitivity analysis demonstrated that contributions of the tested factors to metformin DDI with cimetidine are gastrointestinal transit rate > inhibition of renal OCT2 ≈ inhibition of renal MATEs > inhibition of intestinal OCT3 > intestinal pH > inhibition of hepatic OCT1. Individual contributions of transporters to metformin disposition are renal OCT2 ≈ renal MATEs > intestinal OCT3 > hepatic OCT1 > intestinal PMAT. In conclusion, DDIs of metformin with perpetrators are attributed to integrated effects of inhibitions of these transporters.

Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (P_{app, A-to-B}) across the ARPE-19 monolayer were greater than P_{app, B-to-A}. MK571 or bilirubin significantly decreased P_{app, A-to-B} of fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.

Background/Objectives: Carboxylesterase 1 (CES1) is a key enzyme involved in the bioactivation of ester prodrugs. This study aimed to construct a mechanistic, whole-body, physiologically based pharmacokinetic (PBPK) model to simultaneously predict the pharmacokinetics of CES1-activated prodrugs and their metabolites across different age groups. Methods: A comprehensive whole-body prodrug–metabolite PBPK framework was constructed by integrating age-specific physiological parameters. Oseltamivir and enalapril were evaluated across adult, pediatric, and geriatric populations, whereas cilazapril validation was focused on adult and geriatric cohorts based on clinical data availability. The model was developed and validated in adults, and then extrapolated to pediatric and geriatric populations. Model performance was evaluated by comparing predicted and observed pharmacokinetic parameters, specifically the area under the curve (${AUC}_{0-t}$) and maximum plasma concentration ($C_{max}$), with an acceptance criterion of 0.5- to 2.0-fold error. Results: The majority of observed plasma concentrations fell within the 5th–95th percentiles of predicted profiles. Additionally, for most simulations, the ${AUC}_{0-t}$ and $C_{max}$ were within 0.5- to 2-fold of the observed values. Sensitivity analyses revealed that the exposure of their active metabolites was highly related to the plasma unbound fraction, glomerular filtration rate, and hepatic CES1-mediated bioactivation. Conclusions: This whole-body PBPK framework provides a mechanistic basis for predicting CES1-mediated prodrug disposition across age groups. The framework achieved clinical validation across pediatric, adult, and geriatric populations for oseltamivir and enalapril, and provided proof-of-concept support for extending the approach to cilazapril. This platform may serve as a basis for future pharmacokinetic/pharmacodynamic integration and model-informed dose optimization.

Purpose: To explore causal relationships between kidney function and the risk of senile cataract and primary open-angle glaucoma (POAG) using Mendelian randomization (MR). Methods: Summary statistics for kidney function traits were obtained from the CKDGen consortium to identify genetically predicted chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). Data on senile cataract and POAG were sourced from the FinnGen consortium. Initially, we applied the bidirectional univariate MR method (UVMR) to assess the causal effects between kidney function and the risk of senile cataract and POAG. Inverse-variance weighted method (IVW) served as the primary analysis, supplemented by weighted median and MR-Egger methods. Subsequently, multivariable MR (MVMR) was conducted to validate significant causal associations identified in UVMR. Bioinformatics analyses were conducted through enrichment analysis and a protein–protein interaction network to elucidate potential molecular mechanisms. Results: UVMR showed that higher genetically predicted UACR was associated with an increased risk of senile cataract (IVW OR = 1.29, 95% CI: 1.05 to 1.58, P = 0.016), but no reverse causality was observed. No causal associations were found between CKD or eGFR and cataract, or between kidney function and POAG. MVMR further indicated that the associations of UACR with senile cataract remained robust after adjusting for potential confounders, including eGFR, telomere length, diabetes, hypertension, and smoking. Enrichment analysis highlighted significant associations with retinol metabolism, xenobiotic metabolism by cytochrome P450, and glycine/serine/threonine metabolism pathways. Conclusion: Our results suggested that kidney damage, as measured by UACR, causally increased the risk of cataract, but no causal relationship was found between kidney function and POAG. This study underscores the importance of regular ophthalmic screening for individuals with albuminuria.