VARIABILITY IN METFORMIN PHARMACOKINETICS: INFLUENCE OF CIMETIDINE COADMINISTRATION, GENETIC POLYMORPHISMS, AND AGE

Anoud Sameer Fouad Ailabouni

doi:10.7273/000007311

Metformin is a widely used first-line treatment for type 2 diabetes mellitus (T2DM) in patients aged 10 years and older. Due to its hydrophilic nature, metformin requires cation transporters for its absorption and elimination. Organic cation transporter (OCT) 2, an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells, plays a critical role in the renal secretion of metformin together with multidrug toxin extrusion (MATE) transporters expressed on the apical membrane of renal cells. Metformin pharmacokinetics is associated with high interindividual variability in adults, with limited data available in pediatric populations. The primary objective of this dissertation project was to investigate the influence of external factors, such as the administration of an OCT inhibitor cimetidine, and biological factors, such as age and genetic variants of OCT and MATE, on the pharmacokinetics of metformin and endogenous transporter substrates like N1-methylnicotinamide (NMN). Chapter 1 provided an overview of factors affecting OCT2 expression and activity, which could influence the pharmacokinetics of metformin and endogenous substrates. These factors include sex, age, genetic variants, disease states, and concomitant drugs. The chapter also highlighted innovative approaches, including the application of OCT2 biomarkers and physiologically based pharmacokinetic (PBPK) modeling, to predict OCT2-mediated drug-drug interactions (DDIs). In Chapter 2, the data on the pharmacokinetic cimetidine-metformin study were presented in six Sprague Dawley rats. A metabolomics approach identified metabolites that could predict renal DDIs during the preclinical stages of drug development. In Chapter 3, a clinical pharmacokinetic cimetidine-metformin study was conducted in 16 healthy adults to investigate the effects of cimetidine and genetic variants on metformin pharmacokinetics. The results indicated that cimetidine is primarily inhibiting hepatic OCT1 and, to a lesser extent, renal OCT2. This chapter also utilized PBPK modeling and OCT potential biomarkers (e.g., NMN) to predict the transporters involved in the interaction which further indicates minimal renal-mediated DDI. Genotyping identified key variants in OCT1, OCT2, and MATE2K that could result in statistically significant differences in the magnitude of the interaction. Chapter 4 focused on investigating the mechanisms of the unexpected reduction in NMN plasma concentrations following cimetidine exposure, which contradicted typical OCT2 inhibition. In vitro assays demonstrated that NMN is an OCT1 substrate and that cimetidine inhibits NMN uptake in OCT1-HEK293 cells. Accordingly, NMN can be a potential OCT1 biomarker where cimetidine-mediated OCT1 inhibition may hinder the release of NMN into the systemic circulation, resulting in reduced NMN plasma concentrations. Chapter 5 presented a population pharmacokinetic modeling of metformin plasma concentrations obtained from 36 pediatric patients which revealed high interindividual variability among therapeutic doses. The impact of covariates and genetic variants on metformin pharmacokinetics was assessed. Total body weight (TBW) and estimated glomerular filtration rate (eGFR) were identified as significant factors influencing metformin oral clearance (CL/F). Genetic analysis revealed that OCT3 (rs555754 and rs668871) variants affected the absorption rate constant and CL/F of metformin, whereas an OCT2 variant (rs624249) was associated with CL/F and secretary renal clearance of metformin. In summary, the findings from this dissertation emphasize the importance of considering TBW, eGFR, and transporter genetic variants when optimizing metformin dosing. This personalized approach can enhance the safety and therapeutic efficacy of metformin.

VARIABILITY IN METFORMIN PHARMACOKINETICS: INFLUENCE OF CIMETIDINE COADMINISTRATION, GENETIC POLYMORPHISMS, AND AGE

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