Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

Zamek‐Gliszczynski, Maciej J.; Taub, Mitchell E.; Chothe, Paresh P.; Chu, Xiaoyan; Giacomini, Kathleen M.; Kim, Richard B.; Ray, Adrian S.; Stocker, Sophie L.; Unadkat, Jashvant D.; Wittwer, Matthias; Xia, Cindy Q.; Yee, Sook Wah; Zhang, Lei; Zhang, Yan

doi:10.1002/cpt.1112

Cited by 200 publications

(206 citation statements)

References 101 publications

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“…Likewise, OCT2 genotype data support its role in creatinine renal disposition ( Table ), together with in silico structural modeling of creatinine interactions with variants of OCT2 37 . Conversely, confidence toward the in vivo role of OAT2 is limited by inconsistent in vitro uptake data from OAT2‐transfected cell lines, 38 limited genetic variability, and lack of drugs known or expected to inhibit OAT2 in vivo .…”

Section: Discussionmentioning

confidence: 97%

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Scotcher

Arya

Yang

et al. 2020

CPT Pharmacom & Syst Pharma

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Creatinine is widely used as a biomarker of glomerular filtration, and, hence, renal function. However, transporter-mediated secretion also contributes to its renal clearance, albeit to a lesser degree. Inhibition of these transporters causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The current study developed mechanistic models of creatinine kinetics within physiologically based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional-OCT2 transport (driven by electrochemical gradient). Robustness of creatinine models was assessed by predicting creatinine-drug interactions with 10 perpetrators; performance evaluation accounted for 5% intra-individual variability in serum creatinine. Models showed comparable predictive performances of the maximum steady-state effect regardless of OCT2 directionality assumptions. However, only the bidirectional-OCT2 model successfully predicted the minimal effect of ranitidine. The dynamic nature of models provides clear advantage to static approaches and most advanced framework for evaluating interplay between multiple processes in creatinine renal disposition.

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Section: Discussionmentioning

confidence: 97%

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Scotcher

Arya

Yang

et al. 2020

CPT Pharmacom & Syst Pharma

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“…Some members of the OATP family, such as OATP1B1, OATP1B3, and OATP2B1 (SLCO1B1, SLCO1B3, SLCO2B1 genes, respectively) are highly expressed at the basolateral membrane of hepatocytes, where they play an important role in the uptake of many different substrates [4]. Because of their role in drug uptake and disposition, OATP1B1 and OATP1B3 are considered among the most clinically relevant carriers by ITC guidelines [5,6].…”

Section: Organic Anion-transporting Polypeptides (Oatps)mentioning

confidence: 99%

Role of Genetic Variations in the Hepatic Handling of Drugs

Marin

Serrano

Monte

et al. 2020

IJMS

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The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

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“…Together, these two transporter families comprise approximately 450 individual members, for one-third of which the exact physiological function still remains unclear. Approximately 30 SLC and ABC transporters have been classified as drug transporters as they are capable of transporting a multitude of different drugs and drug metabolites across cell membranes [3][4][5]. These transporters are abundantly expressed in clearance organs, such as the liver and the kidney, which together account for the excretion of the majority of drug molecules [6].…”

Section: Introductionmentioning

confidence: 99%

Use of imaging to assess the activity of hepatic transporters

Hernández-Lozano

Langer

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available. Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach. Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs. ARTICLE HISTORY

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Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

Cited by 200 publications

References 101 publications

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Role of Genetic Variations in the Hepatic Handling of Drugs

Use of imaging to assess the activity of hepatic transporters

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