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Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease

Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptide 1B transporter (OATP1B). CPI plasma baseline was reported to increase with severity of chronic kidney disease (CKD). Further, ratio of CPI area under the plasma concentration‐time curve (AUCR) in the presence...

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Autores principales: Takita, Hiroyuki, Scotcher, Daniel, Chu, Xiaoyan, Yee, Ka Lai, Ogungbenro, Kayode, Galetin, Aleksandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9540787/
https://www.ncbi.nlm.nih.gov/pubmed/35652251
http://dx.doi.org/10.1002/cpt.2672
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author Takita, Hiroyuki
Scotcher, Daniel
Chu, Xiaoyan
Yee, Ka Lai
Ogungbenro, Kayode
Galetin, Aleksandra
author_facet Takita, Hiroyuki
Scotcher, Daniel
Chu, Xiaoyan
Yee, Ka Lai
Ogungbenro, Kayode
Galetin, Aleksandra
author_sort Takita, Hiroyuki
collection PubMed
description Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptide 1B transporter (OATP1B). CPI plasma baseline was reported to increase with severity of chronic kidney disease (CKD). Further, ratio of CPI area under the plasma concentration‐time curve (AUCR) in the presence/absence of OATP1B inhibitor rifampin was higher in patients with CKD compared with healthy participants, in contrast to pitavastatin (a clinical OATP1B probe). This study investigated mechanism(s) contributing to altered CPI baseline in patients with CKD by extending a previously developed physiologically‐based pharmacokinetic (PBPK) model to this patient population. CKD‐related covariates were evaluated in a stepwise manner on CPI fraction unbound in plasma (f(u,p) ), OATP1B‐mediated hepatic uptake clearance (CL(active) ), renal clearance (CL(R) ), and endogenous synthesis (k(syn) ). The CPI model successfully recovered increased baseline and rifampin‐mediated AUCR in patients with CKD by accounting for the following disease‐related changes: 13% increase in f(u,p) , 29% and 39% decrease in CL(active) in mild and moderate to severe CKD, respectively, decrease in CL(R) proportional to decline in glomerular filtration rate, and 27% decrease in k(syn) in severe CKD. Almost complete decline in CPI renal elimination in severe CKD increased its fraction transported by OATP1B, rationalizing differences in the CPI–rifampin interaction observed between healthy participants and patients with CKD. In conclusion, mechanistic modeling performed here supports CKD‐related decrease in OATP1B function to inform prospective PBPK modeling of OATP1B‐mediated drug‐drug interaction in these patients. Monitoring of CPI allows detection of CKD–drug interaction risk for OATP1B drugs with combined hepatic and renal elimination which may be underestimated by extrapolating the interaction risk based on pitavastatin data in healthy participants.
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spelling pubmed-95407872022-10-14 Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease Takita, Hiroyuki Scotcher, Daniel Chu, Xiaoyan Yee, Ka Lai Ogungbenro, Kayode Galetin, Aleksandra Clin Pharmacol Ther Research Coproporphyrin I (CPI) is an endogenous biomarker of organic anion transporting polypeptide 1B transporter (OATP1B). CPI plasma baseline was reported to increase with severity of chronic kidney disease (CKD). Further, ratio of CPI area under the plasma concentration‐time curve (AUCR) in the presence/absence of OATP1B inhibitor rifampin was higher in patients with CKD compared with healthy participants, in contrast to pitavastatin (a clinical OATP1B probe). This study investigated mechanism(s) contributing to altered CPI baseline in patients with CKD by extending a previously developed physiologically‐based pharmacokinetic (PBPK) model to this patient population. CKD‐related covariates were evaluated in a stepwise manner on CPI fraction unbound in plasma (f(u,p) ), OATP1B‐mediated hepatic uptake clearance (CL(active) ), renal clearance (CL(R) ), and endogenous synthesis (k(syn) ). The CPI model successfully recovered increased baseline and rifampin‐mediated AUCR in patients with CKD by accounting for the following disease‐related changes: 13% increase in f(u,p) , 29% and 39% decrease in CL(active) in mild and moderate to severe CKD, respectively, decrease in CL(R) proportional to decline in glomerular filtration rate, and 27% decrease in k(syn) in severe CKD. Almost complete decline in CPI renal elimination in severe CKD increased its fraction transported by OATP1B, rationalizing differences in the CPI–rifampin interaction observed between healthy participants and patients with CKD. In conclusion, mechanistic modeling performed here supports CKD‐related decrease in OATP1B function to inform prospective PBPK modeling of OATP1B‐mediated drug‐drug interaction in these patients. Monitoring of CPI allows detection of CKD–drug interaction risk for OATP1B drugs with combined hepatic and renal elimination which may be underestimated by extrapolating the interaction risk based on pitavastatin data in healthy participants. John Wiley and Sons Inc. 2022-06-28 2022-09 /pmc/articles/PMC9540787/ /pubmed/35652251 http://dx.doi.org/10.1002/cpt.2672 Text en © 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Takita, Hiroyuki
Scotcher, Daniel
Chu, Xiaoyan
Yee, Ka Lai
Ogungbenro, Kayode
Galetin, Aleksandra
Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title_full Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title_fullStr Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title_full_unstemmed Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title_short Coproporphyrin I as an Endogenous Biomarker to Detect Reduced OATP1B Activity and Shift in Elimination Route in Chronic Kidney Disease
title_sort coproporphyrin i as an endogenous biomarker to detect reduced oatp1b activity and shift in elimination route in chronic kidney disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9540787/
https://www.ncbi.nlm.nih.gov/pubmed/35652251
http://dx.doi.org/10.1002/cpt.2672
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