Clinical Assessment of Drug Transporter Inhibition Using Biomarkers: Review of the Literature (2015–2024)

The Journal of Clinical Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 19, 2025

Abstract As part of a narrative review various publications describing the clinical use urine‐ and plasma‐based drug transporter biomarkers, it was determined that utilization coproporphyrin I, hepatic organic anion transporting polypeptide (OATP) 1B1 OATP1B3 biomarker, has been reported for 28 different drug–drug interaction (DDI) perpetrator drugs. Similarly, biomarkers liver cation 1 (isobutyryl‐ l ‐carnitine, N = 7 inhibitors), renal 2 multidrug toxin extrusion proteins (N ‐methylnicotinamide, 13 (OAT) 3 (pyridoxic acid, breast cancer resistance protein (riboflavin, inhibitors) have also described. Increased accompanied by modeling efforts to enable DDI predictions development multiplexed methods facilitate their bioanalysis. Overall, there is consensus exploratory such as I can be integrated into decision trees encompassing in vitro inhibition data, risk assessments, follow‐up Phase studies. Therefore, sponsors leverage evaluate dose‐dependent selected transporters, them jointly with probes deconvolute mechanisms, integrate data packages establish calibrated (biomarker informed) assessment cutoffs. Although biomarker science progressed, reflected its inclusion recently issued International Council Harmonisation guidance document (M12), some still require further validation. There need differentiate specific transporters (e.g., vs OATP1B1 OAT1 OAT3).

Language: Английский

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Is N1-Methylnicotinamide a Good Organic Cation Transporter 2 (OCT2) Biomarker?

Metabolites, Journal Year: 2025, Volume and Issue: 15(2), P. 80 - 80

Published: Jan. 29, 2025

Background/Objectives: The impact of potential precipitant drugs on plasma or urinary exposure endogenous biomarkers is emerging as an alternative approach to evaluating drug–drug interaction (DDI) liability. N1-Methylnicotinamide (NMN) has been proposed a biomarker for renal organic cation transporter 2 (OCT2). NMN synthesized in the liver from nicotinamide by N-methyltransferase (NNMT) and subsequently metabolized aldehyde oxidase (AO). Multiple clinical studies have shown reduction concentration following administration OCT inhibitors such cimetidine, trimethoprim, pyrimethamine, which contrasts with their inhibition clearance OCT2. We hypothesized that OCT1-mediated release hepatocytes inhibited inhibitors. Methods: Re-analysis reported pharmacokinetics without inhibitor was performed. assessed effect cimetidine uptake OCT1-HEK293 cells evaluated confounding effects enzymes involved formation metabolism. Results: A re-analysis previous pharmacokinetic DDI data suggests systemic decreased 17–41% during first 4 h different except dolutegravir. Our findings indicate significantly higher (by 2.5-fold) compared mock cells, suggesting substrate OCT1. Additionally, our results revealed does not inhibit NNMT AO activity. Conclusions: emphasize limitations using OCT2 reveal mechanisms behind levels associated Instead, suggest could be tested further OCT1

Language: Английский

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Organic cation transporters 2 (OCT2): Structure, regulation, functions, and clinical implications

Drug Metabolism and Disposition, Journal Year: 2025, Volume and Issue: unknown, P. 100044 - 100044

Published: Jan. 1, 2025

The SLC22A2 gene encodes organic cation transporter 2 (OCT2), which is predominantly expressed in renal proximal tubule cells. OCT2 critical for the active excretion of various cationic drugs and endogenous metabolites. expression varies across species, with higher levels mice monkeys compared humans rats. human protein consists 555 amino acids contains 12 transmembrane domains. functions as a uniporter, facilitating bidirectional transport cations into tubular cells, driven by inside-negative membrane potential. Its regulated sex hormones, contributing to potential differences Oct2 activity rodents. has been linked tissue toxicity, such cisplatin-induced nephrotoxicity. Factors genetic variants, age, disease states, coadministration drugs, including tyrosine kinase inhibitors, contribute interindividual variability activity. This, turn, impacts systemic exposure elimination substances. Regulatory agencies recommend evaluating drug inhibit through vitro clinical drug-drug interaction (DDI) studies, often using metformin probe substrate. Emerging tools like biomarkers physiologically based pharmacokinetic modeling hold promise predicting OCT2-mediated DDIs. While several biomarkers, N1-methylnicotinamide, have proposed, their reliability DDIs remains uncertain requires further study. Ultimately, better understanding factors influencing essential achieving precision medicine minimizing toxicity. SIGNIFICANCE STATEMENT: Organic (OCT2) secretion xenobiotics substances kidneys. This article offers comprehensive overview distribution, interspecies differences, affecting its activity-critical toxicity Using integrating data models are valuable function implications.

Language: Английский

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From discovery to translation: Endogenous substrates of OAT1 and OAT3 as clinical biomarkers for renal secretory function

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

ABSTRACT The recent ICH M12 guidance on Drug Interaction Studies encourages the use of alternate approaches for predicting drug-drug interaction (DDI) potential new chemical entities. One approach involves biomarkers, which are endogenous substrates drug metabolizing enzymes and transporters (DMET) can be used to assess inhibitory entities during Phase 1 clinical studies. Thus, biomarkers could potentially eliminate need dedicated DDI studies with exogenous probe substrates. Metabolomics, in conjunction vitro and/or vivo preclinical models or studies, biomarker discovery. We developed applied a novel metabolomics-based DMET discovery (MDBD) identify qualify renal organic anion transporter (OAT1) OAT3. Untargeted metabolomics pooled plasma urine samples from pharmacokinetic study using OAT1/3 inhibitor, probenecid, yielded 153 features identified as putative biomarkers. Subsequently, uptake assays processed confirmed 57 these OAT1 OAT3 Finally, 23 were clinically validated through detailed analysis (0-24 h) samples. These either alone part panel, predict OAT1/3-mediated DDIs interindividual variability secretory clearance anions across different populations, thereby enabling translational utility settings. MDBD extended discover other enzymes. SUMMARY Using mechanistic approaches, secretary elimination anions.

Language: Английский

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Precision Medication Based on the Evaluation of Drug Metabolizing Enzyme and Transporter Functions

Precision Clinical Medicine, Journal Year: 2025, Volume and Issue: 8(1)

Published: Jan. 7, 2025

Abstract Pharmacogenomics, therapeutic drug monitoring, and the assessments of hepatic renal function have made significant contributions to advancement individualized medicine. However, their lack direct correlation with protein abundance/non-genetic factors, target concentration, metabolism/excretion significantly limits application in precision therapy. The primary task medicine is accurately determine dosage, which depends on a precise assessment ability handle drugs vivo, metabolizing enzymes transporters are critical determinants disposition body. Therefore, evaluating functions these key assessing capacity predicting concentrations organs. Recent advancements evaluation enzyme transporter using exogenous probes endogenous biomarkers show promise advancing personalized This article aims provide comprehensive overview latest research markers used for functional drug-metabolizing transporters. It also explores marker omics systematically functions, thereby laying foundation pharmacotherapy.

Language: Английский

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Virtual twin approach using physiologically based pharmacokinetic modelling in hospitalized patients treated with apixaban or rivaroxaban

British Journal of Clinical Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Aims In a large cohort of hospitalized patients, previously validated physiologically based pharmacokinetic (PBPK)‐based models for apixaban and rivaroxaban are being assessed their performance in predicting individual pharmacokinetics, aiming to identify patients at high risk under‐ or overdosing on demographic, physiological CYP‐related phenotypic characteristics. Methods Clinical data were collected from treated with ( n = 100) the Geneva University Hospitals (HUG). These recruited OptimAT trial (NCT03477331). PBPK modelling created virtual twins each patient, integrating kidney function, P‐glycoprotein (Pgp) cytochrome P450 (CYP450) 3A phenotyping. Individual PK profiles simulated every patient compared actual drug exposure, as LC/MS–MS. Results Mean fold error (MFE) (95% CI) demographic function was within pre‐required bioequivalency criteria 1.10 (1.04–1.16) 0.97 (0.93–1.02), respectively. Adding Pgp CYP3A phenotypes led slight overprediction 1.25 (1.17–1.33) 1.30 (1.21–1.39), but bleeding correctly predicted MFEs 0.90 (0.76–1.04) 1.15 (1.11–1.20). Conclusions model incorporating characteristics can accurately predict, criteria, an individual's plasma exposure. The added value predictive need be further explored, although higher may benefit. This innovative approach represents important step towards application bedside.

Language: Английский

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Pyridoxic Acid as Endogenous Biomarker of Renal Organic Anion Transporter Activity: Population Variability and Mechanistic Modeling to Predict Drug–Drug Interactions

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Language: Английский

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Recent advances in mass spectrometry-based bioanalytical methods for endogenous biomarkers analysis in transporter-mediated drug-drug interactions

Journal of Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown, P. 101289 - 101289

Published: April 1, 2025

Language: Английский

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Artificial intelligence modeling of biomarker‐based physiological age: Impact on phase 1 drug‐metabolizing enzyme phenotypes

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 14, 2024

Abstract Age and aging are important predictors of health status, disease progression, drug kinetics, effects. The purpose was to develop ensemble learning‐based physiological age (PA) models for evaluating metabolism. National Health Nutrition Examination Survey (NHANES) data were modeled with learning obtain two PA models, PA‐M1 PA‐M2. included body composition, blood urine biomarkers, variables as predictors. PA‐M2 had urine‐derived Activity phenotypes cytochrome‐P450 (CYP) CYP2E1, CYP1A2, CYP2A6, xanthine oxidase (XO), N‐acetyltransferase‐2 (NAT‐2) telomere attrition assessed. Bayesian networks used mechanistic systems pharmacology model structures PA. study n = 22,307 NHANES participants (51.5% female, mean 46.0 years, range: 18–79 years). distributions greater dispersion across strata a right skew younger left older strata. There no evidence algorithmic bias based on sex or race/ethnicity. Klotho, lean mass, glycohemoglobin, systolic pressure the top four PA‐M1. Glycohemoglobin, serum creatinine, total cholesterol, creatinine also performed satisfactorily in independent validation. Model‐predicted associated XO, NAT‐2 activity. Telomere Ensemble provide robust assessments from easily obtained biomarkers. is Phase I drug‐metabolizing enzyme phenotypes.

Language: Английский

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