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Elucidation of Carboxylesterase Mediated Pharmacokinetic Interactions between Irinotecan and Oroxylin A in Rats via Physiologically Based Pharmacokinetic Modeling

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Abstract

Purpose

Our previous screening studies identified Oroxylin A (OXA) as a strong inhibitor on the carboxyolesterase mediated hydrolysis of irinotecan to SN-38. The current study employed a whole-body physiologically based pharmacokinetic (PBPK) modeling approach to investigate the underlying mechanisms of the carboxylesterase-mediated pharmacokinetics interactions between irinotecan and OXA in rats.

Methods

Firstly, rats received irinotecan intravenous treatment at 35 μmol/kg without or with oral OXA pretreatment (2800 μmol/kg) daily for 5 days. On day 5, blood and tissues were collected for analyses of irinotecan/SN-38 concentrations and carboxylesterase expression. In addition, effects of OXA on the enzyme kinetics of irinotecan hydrolysis and unbound fractions of irinotecan and SN-38 in rat plasma, liver and intestine were also determined. Finally, a PBPK model that integrated the physiological parameters, enzyme kinetics, and physicochemical properties of irinotecan and OXA was developed.

Results

Our PBPK model could accurately predict the pharmacokinetic profiles of irinotecan/SN-38, with AUC0-6h and Cmax values within ±27% of observed values. When OXA was included as a carboxylesterase inhibitor, the model could also predict the irinotecan/SN-38 plasma concentrations within twofold of those observed. In addition, the PBPK model indicated inhibition of carboxylesterase-mediated hydrolysis of irinotecan in the intestinal mucosa as the major underlying mechanism for the pharmacokinetics interactions between irinotecan and OXA.

Conclusion

A whole-body PBPK model was successfully developed to not only predict the impact of oral OXA pretreatment on the pharmacokinetics profiles of irinotecan but also reveal its inhibition on the intestinal carboxylesterase as the major underlying mechanism.

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Abbreviations

AUC :

area under curve

CAR :

constitutive androstane receptor

CES :

Carboxylesterase

Cmax :

peak plasma concentration

hCE1 :

human CES1

hCE2 :

human CES2

HDI :

herb-drug interaction

IS :

internal standard

IV :

intravenous

K i :

inhibition constants

K m :

Michaelis constant

OAG :

oroxylin A-7-O-glucuronide glucuronide

OXA :

oroxylin A

PO :

oral

PBPK :

physiologically based pharmacokinetic

PXR :

pregnane x receptor

PK :

pharmacokinetics

RS :

Radix Scutellariae

V max :

Maximum velocity

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Acknowledgments

This work was supported by the General Research Fund of Hong Kong Research Grants Council (Project number: 14108119). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Author notes

  1. Jun Zhang and Yufeng Zhang These authors contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR

    Jun Zhang, Yufeng Zhang, Yuen Sze Lai, Qianbo Song, Min Xiao, Xiaoyu Ji, Xiaoyu Yan & Zhong Zuo

  2. State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    Zhong Zuo

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  1. Jun Zhang
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Zhang, J., Zhang, Y., Lai, Y.S. et al. Elucidation of Carboxylesterase Mediated Pharmacokinetic Interactions between Irinotecan and Oroxylin A in Rats via Physiologically Based Pharmacokinetic Modeling. Pharm Res 40, 2627–2638 (2023). https://doi.org/10.1007/s11095-023-03590-1

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