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Unravelling the Hepatic Elimination Mechanisms of Colistin

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Abstract

Purpose

Colistin is an antibiotic which is increasingly used as a last-resort therapy in critically-ill patients with multidrug resistant Gram-negative infections. The purpose of this study was to evaluate the mechanisms underlying colistin’s pharmacokinetic (PK) behavior and to characterize its hepatic metabolism.

Methods

In vitro incubations were performed using colistin sulfate with rat liver microsomes (RLM) and with rat and human hepatocytes (RH and HH) in suspension. The uptake of colistin in RH/HH and thefraction of unbound colistin in HH (fu,hep) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CLh) of colistin.

Results

Slow metabolism was detected in RH/HH, with intrinsic clearance (CLint) values of 9.34± 0.50 and 3.25 ± 0.27 mL/min/kg, respectively. Assuming the well-stirred model for hepatic drug elimination, the predicted rat CLh was 3.64± 0.22 mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CLh was 91.5 ± 8.83 mL/min, which was within two-fold of the reported plasma clearance in healthy volunteers. When colistin was incubated together with the multidrug resistance-associated protein (MRP/Mrp) inhibitor benzbromarone, the intracellular accumulation of colistin in RH/HH increased significantly.

Conclusion

These findings indicate the major role of hepatic metabolism in the non-renal clearance of colistin, while MRP/Mrp-mediated efflux is involved in the hepatic disposition of colistin. Our data provide detailed quantitative insights into the hereto unknown mechanisms responsible for non-renal elimination of colistin.

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Abbreviations

AUC:

Area under the curve

CLh :

Hepatic clearance

CLp :

Plasma clearance

CLint

intrinsic clearance

CLmet :

Intrinsic clearance via hepatic metabolism

Css,avg :

Average steady state plasma colistin concentration

\({\mathrm{CL}}_{\mathrm{in}}^s\) :

Intrinsic clearance via sinusoidal influx

\({\mathrm{CL}}_{\mathrm{ef}}^s\) :

Intrinsic clearance via sinusoidal efflux

CMS:

Colistin methanesulphonate

CV:

Coefficient of variation

F:

CMS molar fraction that becomes systemically available as colistin (in vivo)

fu :

Fraction unbound in plasma

fu,hep :

Fraction unbound in hepatocytes

HPGL:

Number of hepatocytes per gram liver

HH:

Human hepatocytes

IVIVE:

In vitro-in vivo extrapolation

MIU:

Million international units

MRP/Mrp:

Multidrug resistance-associated proteins

OATP:

Organic anion transporting polypeptides

PK:

Pharmacokinetic

RH:

Rat hepatocytes

RLM:

Rat liver microsomes

SCH:

Sandwich cultured hepatocytes

SCRH:

Sandwich cultured rat hepatocytes

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Acknowledgments

Bing Qi received a PhD scholarship received from China Scholarship Council (CSC).

Funding

This research was supported in part by internal funds of the Drug Delivery and Disposition research unit of the KU Leuven Department of Pharmaceutical and Pharmacological Sciences.

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Authors and Affiliations

  1. Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium

    Bing Qi, Tom De Vocht, Neel Deferm, Pieter Van Brantegem, Getahun B. Abza, Nina Nauwelaerts & Pieter Annaert

  2. The Second Affiliated Hospital, Xi’an Medical University, Xi’an, Shaanxi, China

    Bing Qi

  3. Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium

    Matthias Gijsen & Isabel Spriet

  4. Pharmacy Department, University Hospitals Leuven, Leuven, Belgium

    Matthias Gijsen & Isabel Spriet

  5. Clinical Infectious and Inflammatory Disorders, KU Leuven Department of Microbiology and Immunology; Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Joost Wauters

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  1. Bing Qi
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Qi, B., Gijsen, M., De Vocht, T. et al. Unravelling the Hepatic Elimination Mechanisms of Colistin. Pharm Res 40, 1723–1734 (2023). https://doi.org/10.1007/s11095-023-03536-7

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