Effects of Low-Dose Escherichia coli Lipopolysaccharide-Induced Endotoxemia on Morphine Pharmacokinetics in an Animal Model.

Abstract

OBJECTIVE: Systemic inflammation may change the bioavailability and pharmacokinetics of opioids. However, there are insufficient data on morphine pharmacokinetics in mild inflammatory conditions. This study aimed to determine the pharmacokinetics of morphine during low-dose endotoxemia in rabbits. DESIGN: In two experiments (separated by a 14-day washout period), 10 rabbits received intravenous morphine at a dose of 3 mg/kg. In the second set of experiments, morphine infusion was preceded by low-dose endotoxemia induced with lipopolysaccharide (Escherichia coli 0111: B4) at a dose of 5 µg/kg. The kinetics of systemic morphine concentrations and chosen physiological parameters were measured at specific time intervals up to 6 hours after morphine administration. RESULTS: In endotoxemia, decreased elimination half-life (P = 0.017), mean residence time (P = 0.022), and volume of distribution (P = 0.037) as well as an increased elimination rate constant (P = 0.013) and total body clearance (P = 0.023) were noted. The inverse linear correlation between morphine clearance versus the percentage (%) change in body temperature and pulse rate observed under control conditions was abolished under endotoxemia. CONCLUSIONS: Low-dose endotoxemia is correlated with significant alterations in morphine pharmacokinetics in rabbits, leading to the faster elimination of the drug. CLINICAL IMPLICATIONS: These findings may have important implications in patients with low-grade inflammation and imply the need to modify morphine dosing regimens to ensure optimal analgesia. The issue warrants further experimental and clinical investigation.