Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation

Li, Yang; Talebi, Zahra; Chen, Xihui; Sparreboom, Alex; Hu, Shuiying

doi:10.3390/molecules26185500

Cited by 21 publications

(16 citation statements)

References 101 publications

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“…103,104 Although this approach is informative for identification of DDIs, experimental execution is complex and requires administration of multiple drugs. In contrast, endogenous transporter substrate biomarkers 105 overcome some of these challenges. More specifically, transporter biomarkers do not require additional compound administration, can easily assess baseline characteristics, can be measured over longer periods of time, and require a low volume of blood.…”

Section: Experimental Approaches To Investigate Regulation Of Transpo...mentioning

confidence: 99%

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

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Membrane transport proteins are involved in the absorption, disposition, efficacy, and/or toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.Transport proteins of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies are widely recognized as key determinants of the absorption, distribution, and excretion of many endogenous compounds and xenobiotics, including drugs, bile acids, hormones, and nutrients, which may thereby directly or indirectly impact medication efficacy and/or safety. Not surprisingly, intersubject variability in drug response due to transporters has been attributed to altered transporter function in organs, such as the intestine, liver, and kidneys. 1,2 Mechanisms of alterations in drug transporter activity have focused primarily on (i) differences in gene expression and/ or protein abundance due to genetic polymorphisms; and (ii) drug-drug interactions (DDIs) predominantly involving direct

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Section: Experimental Approaches To Investigate Regulation Of Transpo...mentioning

confidence: 99%

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Brouwer

Evers

Hayden

et al. 2022

Clin Pharma and Therapeutics

Self Cite

View full text Add to dashboard Cite

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“…One way is the use of probe-drug cocktails, including several transporter substrates without mutual interaction, which are administered together with the drug candidate. This approach has been successfully used in the past with cytochrome P450-related DDIs and the field seems to be rapidly already emerging also in the case of the most common drug carriers (142)(143)(144)(145). This gained knowledge should also be applied to the interactions at the BBB level.…”

Section: Prospectsmentioning

confidence: 99%

Pharmacoproteomics of Brain Barrier Transporters and Substrate Design for the Brain Targeted Drug Delivery

et al. 2022

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One of the major reasons why central nervous system (CNS)-drug development has been challenging in the past, is the barriers that prevent substances entering from the blood circulation into the brain. These barriers include the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), blood-cerebrospinal fluid barrier (BCSFB), and blood-arachnoid barrier (BAB), and they differ from each other in their transporter protein expression and function as well as among the species. The quantitative expression profiles of the transporters in the CNS-barriers have been recently revealed, and in this review, it is described how they affect the pharmacokinetics of compounds and how these expression differences can be taken into account in the prediction of brain drug disposition in humans, an approach called pharmacoproteomics. In recent years, also structural biology and computational resources have progressed remarkably, enabling a detailed understanding of the dynamic processes of transporters. Molecular dynamics simulations (MDS) are currently used commonly to reveal the conformational changes of the transporters and to find the interactions between the substrates and the protein during the binding, translocation in the transporter cavity, and release of the substrate on the other side of the membrane. The computational advancements have also aided in the rational design of transporter-utilizing compounds, including prodrugs that can be actively transported without losing potency towards the pharmacological target. In this review, the state-of-art of these approaches will be also discussed to give insights into the transporter-mediated drug delivery to the CNS.

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“…In this regard, the discovery of endogenous biomarkers that are substrates of corresponding drug transporters (Li et al, 2021) and can subsequently be used in both clinical and pre-clinical stages becomes intriguing as a complementary approach to assess transporter-mediated DDIs (Chu et al, 2018;Muller et al, 2018). For example, plasma coproporphyrin I and III (CP-I and III) levels in monkeys are significantly elevated by administering Oatp inhibitors cyclosporin A or rifampicin (Shen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Elimination Pathways and the Feasibility of Endogenous Metabolites as Biomarkers of Organic Anion Transporter 1/3 Inhibition in Cynomolgus Monkeys

et al. 2023

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Organic anion transporters 1 and 3 (OAT1/3) occupy a key role in mediating renal elimination. Kynurenic acid (KYNA) was previously discovered as an effective endogenous biomarker to assess drug-drug interaction (DDI) for OAT inhibitors. Here, further in vitro and in vivo investigation was performed to characterize the elimination routes and feasibility of KYNA, along with other reported endogenous metabolites, as biomarkers of Oat1/3 inhibition in bile duct-cannulated (BDC) cynomolgus monkeys.Our results suggested KYNA is a substrate of OAT1/3 and OAT2, but not OCT2, MATE1/2K, or NTCP, and it shares comparable affinities between OAT1 and OAT3.Renal and biliary excretions, and plasma concentration-time profiles of KYNA, pyridoxic acid (PDA), homovanillic acid (HVA), and coproporphyrin I (CP-I), were assessed in BDC monkeys dosed with either probenecid (PROB) at 100 mg/kg or the control vehicle. Renal excretion of KYNA, PDA, and HVA was determined to be the major elimination route. The maximum plasma concentration (C max ) and AUC 0-24h of KYNA were about 11.6 and 3.7-fold higher in the PROB group than in the vehicle group. Renal clearance (CL r ) of KYNA decreased by 3.2-fold, but biliary clearance (CL bile ) was not altered after PROB administration. A similar trend was observed for PDA and HVA.Interestingly, an elevation of plasma concentration and reduction of CP-I CL bile were observed after PROB treatment, which suggested inhibition of the CP-I Oatp-Mrp2 transport axis by PROB. Overall, our results indicated that KYNA could potentially facilitate early and reliable assessment of DDI liabilities of Oat inhibition in monkeys.

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Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation

Cited by 21 publications

References 101 publications

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Regulation of Drug Transport Proteins—From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium

Pharmacoproteomics of Brain Barrier Transporters and Substrate Design for the Brain Targeted Drug Delivery

Characterization of Elimination Pathways and the Feasibility of Endogenous Metabolites as Biomarkers of Organic Anion Transporter 1/3 Inhibition in Cynomolgus Monkeys

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