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Title: Effects of sepsis on the pharmacokinetics of selected drugs with different hepatic extraction ratios in mice


In this study, we investigated for the first time the influence of decompensated sepsis on the pharmacokinetics of drugs eliminated by hepatic metabolism: ibuprofen – with low and verapamil – with high hepatic extraction ratio, taking into account their enantiomeric structures. The pharmacokinetic studies were carried out in mice, 20 h after the sepsis induction procedure (CLP). Racemic drugs were administrated intravenously in a dose of 10 mg/kg - ibuprofen and 1 mg / kg – verapamil. Sepsis affected the pharmacokinetics of both drugs. In the case of ibuprofen, the enzymatic inversion of pharmacologically inactive R(-)- into the active S(+)- enantiomer was significantly inhibited and a slight decrease in CLmet of both enantiomers was observed, which led to an increase of t0,5. A reduction of Vdss and a slight increase of fu were also observed. Physiologically-based pharmacokinetic (PBPK) modeling and simulations of ibuprofen concentrations in humans have demonstrated the important role of plasma protein binding in the disposition of this drug. In the case of verapamil, sepsis decreased the CLmet of both enantiomers, which significantly prolonged their t0,5 and increased AUC. Sepsis lowered the Vdss and fu of this drug. PBPK modeling revealed the appearance of verapamil metabolism in spleens of septic mice. Simulations of verapamil concentrations in humans have confirmed that d ; ecompensated sepsis may increase patients' exposure to this drug, increasing its AUC in plasma and kidneys. These types of PBPK models can be used to predict the pharmacokinetics and modify the dosage of drugs with similar PK properties used in sepsis.

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2 - studia doktoranckie

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Rada Dyscypliny Nauki farmaceutyczne


Wyska, Elżbieta

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tylko w bibliotece

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Mar 25, 2024

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Jan 23, 2023

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ZB-136386 Mar 25, 2024


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