Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system

Abstract Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients...

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Autores principales:	Tomoki Imaoka, Weize Huang, Sara Shum, Dale W. Hailey, Shih-Yu Chang, Alenka Chapron, Catherine K. Yeung, Jonathan Himmelfarb, Nina Isoherranen, Edward J. Kelly
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/db5ac2fbd58248ce8a1251ee6b9e7c7a
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spelling	oai:doaj.org-article:db5ac2fbd58248ce8a1251ee6b9e7c7a2021-11-08T10:56:15ZBridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system10.1038/s41598-021-00338-y2045-2322https://doaj.org/article/db5ac2fbd58248ce8a1251ee6b9e7c7a2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00338-yhttps://doaj.org/toc/2045-2322Abstract Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration–time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.Tomoki ImaokaWeize HuangSara ShumDale W. HaileyShih-Yu ChangAlenka ChapronCatherine K. YeungJonathan HimmelfarbNina IsoherranenEdward J. KellyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tomoki Imaoka Weize Huang Sara Shum Dale W. Hailey Shih-Yu Chang Alenka Chapron Catherine K. Yeung Jonathan Himmelfarb Nina Isoherranen Edward J. Kelly Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
description	Abstract Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration–time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.
format	article
author	Tomoki Imaoka Weize Huang Sara Shum Dale W. Hailey Shih-Yu Chang Alenka Chapron Catherine K. Yeung Jonathan Himmelfarb Nina Isoherranen Edward J. Kelly
author_facet	Tomoki Imaoka Weize Huang Sara Shum Dale W. Hailey Shih-Yu Chang Alenka Chapron Catherine K. Yeung Jonathan Himmelfarb Nina Isoherranen Edward J. Kelly
author_sort	Tomoki Imaoka
title	Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
title_short	Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
title_full	Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
title_fullStr	Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
title_full_unstemmed	Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
title_sort	bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/db5ac2fbd58248ce8a1251ee6b9e7c7a
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Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system

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