Unravelling the Hepatic Elimination Mechanisms of Colistin.

Autor: Qi B; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.; The Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, China., Gijsen M; Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.; Pharmacy Department, University Hospitals Leuven, Leuven, Belgium., De Vocht T; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium., Deferm N; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium., Van Brantegem P; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium., Abza GB; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium., Nauwelaerts N; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium., Wauters J; Clinical Infectious and Inflammatory Disorders, KU Leuven Department of Microbiology and Immunology; Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium., Spriet I; Clinical Pharmacology and Pharmacotherapy, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.; Pharmacy Department, University Hospitals Leuven, Leuven, Belgium., Annaert P; Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. pieter.annaert@kuleuven.be.
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2023 Jul; Vol. 40 (7), pp. 1723-1734. Date of Electronic Publication: 2023 May 31.
DOI: 10.1007/s11095-023-03536-7
Abstrakt: 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 (f u,hep ) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CL h ) of colistin.
Results: Slow metabolism was detected in RH/HH, with intrinsic clearance (CL int ) 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 CL h was 3.64± 0.22 mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CL h 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.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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