Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro–In Vivo Scaling of Hepatic Uptake Clearance

De Bruyn, Tom; Ufuk, Ayşe; Cantrill, Carina; Kosa, Rachel E.; Bi, Yi-an; Niosi, Mark; Modi, Sweta; Rodrigues, A. David; Tremaine, Larry M.; Varma, Manthena V.S.; Galetin, Aleksandra; Houston, J. Brian

doi:10.1124/dmd.118.081315

Cited by 53Drug Transport and Resistance MechanismsPharmacogenetics and Drug MetabolismAnimal testing and alternatives

Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro–In Vivo Scaling of Hepatic Uptake Clearance

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De Bruyn, Tom, Ufuk, Ayşe, Cantrill, Carina, Kosa, Rachel E., Bi, Yi-an, Niosi, Mark, Modi, Sweta, Rodrigues, A. David +4 more·2018·Drug Metabolism and Disposition

DOI 10.1124/dmd.118.081315

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Abstract

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species, with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a range similar to human parameters and good predictions from respective hepatocyte parameters (with 2.7- and 3.8-fold bias on average, respectively). The use of cross-species empirical scaling factors (determined from cynomolgus monkey data either as the data set average or individual drug values) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current data set between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance.

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Monkeys are a valuable model for verification of hepatic disposition for transported molecules, particularly for substrates of OATP transporter.
“It has also emerged that monkeys are a valuable model for the verification of hepatic disposition for transported molecules [44] particularly for substrates of the organic anion transporting polypeptide transporter [35].”
From Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies (2019) · cites this paper as [35]
Human clearance predictions may be improved with cross-species empirical scaling factors when active uptake is involved.
“The involvement of active uptake in hepatic clearance can be flagged by the Extended Clearance Classification System, and in such cases measurements in hepatocyte models may be useful [34] and human clearance predictions may be improved with cross-species empirical scaling factors [35].”
From Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies (2019) · cites this paper as [35]

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Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys
Takahashi, T., Ohtsuka, T., Yoshikawa, T., et al. (2013) · Drug Metabolism and Disposition · doi:10.1124/dmd.113.052753 · Cited by 36 · see citing works
Evaluation of [18F]pitavastatin as a positron emission tomography tracer for in vivo organic transporter polypeptide function
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Authors: De Bruyn, T., Ufuk, A., Cantrill, C., Kosa, R. E., Bi, Y.-A., Niosi, M., Modi, S., Rodrigues, A. D., Tremaine, L. M., Varma, M. V. S., Galetin, A., & Houston, J. B.
Affiliations: University of Manchester (GB)
Pfizer (United Kingdom) (GB)
Corresponding author: Houston, J. Brian
ORCID: Cantrill, Carina
Niosi, Mark
Varma, Manthena V.S.
Galetin, Aleksandra
Houston, J. Brian
Venue: Drug Metabolism and Disposition
Publisher: Elsevier BV
Published: 2018-07
Volume: 46
Issue: 7
Pages: 989-1000
ISSN: 0090-9556 (ISSN-L)
DOI: 10.1124/dmd.118.081315
OpenAlex: W2802801850
Cited by: 53
References: 67
Citations by year: 2026: 5 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 12 · 2019: 6 · 2018: 3
FWCI: 2.63
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Drug Metabolism and Disposition (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
Funders: Eli Lilly and Company
Pfizer
GlaxoSmithKline
University of Manchester
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: organic anion transporting polypeptides, Macaca fascicularis, hepatocyte uptake, passive diffusion, rifamycin SV, intracellular binding, preclinical models, rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, valsartan
MeSH terms: Adult, Animals, Biological Transport, Pharmaceutical Preparations, Female, Humans, Kinetics, Liver, Macaca fascicularis, Metabolic Clearance Rate, Peptides, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hepatocytes, Organic Anion Transporters

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Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro–In Vivo Scaling of Hepatic Uptake Clearance

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