Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics
The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xen...
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| Published in | Drug metabolism and disposition Vol. 46; no. 11; pp. 1692 - 1702 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.11.2018
American Society for Pharmacology and Experimental Therapeutics, Inc The American Society for Pharmacology and Experimental Therapeutics |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0090-9556 1521-009X 1521-009X |
| DOI | 10.1124/dmd.118.082958 |
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| Abstract | The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell–derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive “human-like” in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future. |
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| AbstractList | The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell–derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive “human-like” in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future. The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell-derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive "human-like" in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future.The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell-derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive "human-like" in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future. |
| Author | Bajaj, Piyush Xiao, Guangqing Yucha, Robert Chowdhury, Swapan K. Kelly, Edward J. |
| Author_xml | – sequence: 1 givenname: Piyush surname: Bajaj fullname: Bajaj, Piyush email: Piyush.Bajaj@takeda.com – sequence: 2 givenname: Swapan K. surname: Chowdhury fullname: Chowdhury, Swapan K. – sequence: 3 givenname: Robert surname: Yucha fullname: Yucha, Robert – sequence: 4 givenname: Edward J. surname: Kelly fullname: Kelly, Edward J. – sequence: 5 givenname: Guangqing surname: Xiao fullname: Xiao, Guangqing |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30076203$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2018 American Society for Pharmacology and Experimental Therapeutics Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics. Copyright Lippincott Williams & Wilkins Ovid Technologies Nov 1, 2018 Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics 2018 |
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| Keywords | ciPTEC-OAT3 OCT ciPTEC-OAT1 HK UGT SLC MPS EMA MDCK PEPT AA BCRP UDP P-gp iPSC SV40T AUC-ROC NCE ZO-3 TCA ZO-1 PTC PDMS ABC FDA LLC-PK1 OAT IVIVE MATE-1 MATE-2K ATCC KIM-1 2D ciPTEC DDIs HPTC P450 OCTN1 OCTN2 RPTEC TERT1 MRP2 SGLT2 MRP4 ECM 3D GGT URAT1 PAH ITC PK |
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| SubjectTerms | Animals Biological Transport - physiology Biotransformation Cell culture Drug development Drug discovery Drug Discovery - methods Drugs Efflux Enzymes Humans Kidney Tubules, Proximal - metabolism Kidneys Metabolism Pharmaceutical industry Pharmaceuticals Prescription drugs Regulatory agencies Special Section – New Models in Drug Metabolism and Transport Stem cells Technology assessment Toxicity Xenobiotics Xenobiotics - metabolism |
| Title | Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics |
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