Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration

Abstract

Severely ill patients often require total parenteral nutrition including intravenous lipid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed. Midazolam in the VLDL fraction was only 0.246 microgram.ml-1, whereas the total plasma concentration averaged 1.101 micrograms.ml-1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 micrograms.ml-1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg.dl-1 and VLDL-triglycerides from 77 to 155 mg.dl-1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg.dl-1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 microgram.ml-1, 0.130 micrograms.ml-1, and 1.265 micrograms.ml-1, respectively. Cholesterol and albumin concentrations were not affected. The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.

Inhibitory Effects of Amino-Acid Fluids on Drug Binding to Site II of Human Serum Albumin in Vitro

“…However, little information is available on the drug-parenteral nutrition fluid interaction, most notably with respect to the change in protein binding of the drug. [21][22][23][24][25] This study was undertaken to evaluate the effects of parenteral nutrition fluids, especially amino-acid fluids, on protein binding to drugs in vitro. The present findings on the interaction between amino-acid fluids and drugs were well explained based on the concept of binding sites.…”

Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients

“…Most patients who receive PN may also take some therapeutic drugs, leading to potential interactions that may contribute to adverse events. Surprisingly, there are very few published studies on the interaction of PN fluids with therapeutic drugs, and most of them do not focus on protein binding [102,166-169]. …”