Transporter-mediated drug–drug interactions: advancement in models, analytical tools, and regulatory perspective

Jala, Aishwarya; Ponneganti, Srikanth; Vishnubhatla, Devi Swetha; Bhuvanam, Gayathri; Mekala, P.; Varghese, Bincy; Radhakrishnanand, P.; Adela, Ramu; Murty, Upadhyayula Suryanarayana; Borkar, Roshan M.

doi:10.1080/03602532.2021.1928687

Cited by 9 publications

(13 citation statements)

References 215 publications

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“…Mechanistically, most of these DDIs can be linked directly to effects of a select set of xenobiotic transporters that are critically important in mediating drug disposition patterns. These transporters include OATPs, OATs, OCTs, and MATEs, and current regulatory requirements [104] propose an integrated approach to assess DDIs and the potential of a new molecular entity, however, the current in vitro approach is rather conservative and may result in false-positive prediction and subsequently large number of traditional clinical DDIs studies using probe drugs. There is a need to an efficient and cost-effective solution and identify alternative approaches that could help facilitate the prediction of DDIs in early stages of drug development.…”

Section: Discussionmentioning

confidence: 99%

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

Talebi

Chen

et al. 2021

Molecules

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Membrane transporters play an important role in the absorption, distribution, metabolism, and excretion of xenobiotic substrates, as well as endogenous compounds. The evaluation of transporter-mediated drug-drug interactions (DDIs) is an important consideration during the drug development process and can guide the safe use of polypharmacy regimens in clinical practice. In recent years, several endogenous substrates of drug transporters have been identified as potential biomarkers for predicting changes in drug transport function and the potential for DDIs associated with drug candidates in early phases of drug development. These biomarker-driven investigations have been applied in both preclinical and clinical studies and proposed as a predictive strategy that can be supplanted in order to conduct prospective DDIs trials. Here we provide an overview of this rapidly emerging field, with particular emphasis on endogenous biomarkers recently proposed for clinically relevant uptake transporters.

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Section: Discussionmentioning

confidence: 99%

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

Talebi

Chen

et al. 2021

Molecules

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“…Transport proteins are essential determinants of pharmacokinetics and drug effects. [1][2][3][4][5][6] Transporter-mediated drug-drug interactions (DDIs) can cause substantial changes in the victim's drug pharmacokinetics as well as in desired and adverse effects. [1][2][3][4][5][6] Therefore, comprehensive in vitro studies are conducted before drug approval in order to characterize drugs as substrates and…”

mentioning

confidence: 99%

“…This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE-and OAT-mediated DDIs.Transport proteins are essential determinants of pharmacokinetics and drug effects. [1][2][3][4][5][6] Transporter-mediated drug-drug interactions (DDIs) can cause substantial changes in the victim's drug pharmacokinetics as well as in desired and adverse effects. [1][2][3][4][5][6] Therefore, comprehensive in vitro studies are conducted before drug approval in order to characterize drugs as substrates and…”

mentioning

confidence: 99%

“…[1][2][3][4][5][6] Transporter-mediated drug-drug interactions (DDIs) can cause substantial changes in the victim's drug pharmacokinetics as well as in desired and adverse effects. [1][2][3][4][5][6] Therefore, comprehensive in vitro studies are conducted before drug approval in order to characterize drugs as substrates and…”

mentioning

confidence: 99%

“…Transport proteins are essential determinants of pharmacokinetics and drug effects 1–6 . Transporter‐mediated drug‐drug interactions (DDIs) can cause substantial changes in the victim's drug pharmacokinetics as well as in desired and adverse effects 1–6 .…”

mentioning

confidence: 99%

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A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

Gessner

Müller

Wenisch

et al. 2023

Clin Pharma and Therapeutics

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Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2‐K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intrastudy comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of ten previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with four inhibitors of transport proteins [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N‐oxide were both sensitive and specific (median log2‐fold changes ‐1.18 in estimated renal elimination and ‐0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2‐fold changes ‐3.77 and ‐2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE‐ and OAT‐mediated drug‐drug interactions.

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New Biomarkers for Renal Transporter‐Mediated Drug–Drug Interactions: Metabolomic Effects of Cimetidine, Probenecid, Verapamil, and Rifampin in Humans

Gessner,

König,

Wenisch

et al. 2024

Clin Pharma and Therapeutics

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The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2‐K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug–drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE‐ or OAT‐mediated DDIs. For OCT2/MATEs, 5‐amino valeric acid betaine (median log2‐fold change of estimated renal elimination: −3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7‐methyluric acid and cinnamoylglycine (median log2‐fold changes −3.10 and −1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter‐mediated DDIs.

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Transporter-mediated drug–drug interactions: advancement in models, analytical tools, and regulatory perspective

Cited by 9 publications

References 215 publications

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

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

A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

New Biomarkers for Renal Transporter‐Mediated Drug–Drug Interactions: Metabolomic Effects of Cimetidine, Probenecid, Verapamil, and Rifampin in Humans

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