Abstracts Category : Other

The Effect of Therapeutic Hypothermia on Drug Metabolism and Transport: Clinical and Pre-Clinical Investigations

by Kacey Anderson

Therapeutic hypothermia, active cooling of a patient to a core body temperature of 32-34C, is a neuroprotective therapy that is employed in critically ill patients to prevent further neuronal damage following an acute injury. While undergoing therapeutic hypothermia, critically ill patients are also administered a multitude of medications, which puts them at high risk for adverse drug events. The majority of these drugs undergo hepatic elimination via cytochrome P450 (CYP450) metabolic pathways and/or many also undergo active transport via the ATP-Binding Cassette (ABC) drug transporter pathways. In order to safely and effectively treat this critically ill population, it is imperative to understand how therapeutic hypothermia effects drug metabolism and drug transport. Therefore, the overarching aim of this dissertation was to expand what is currently known about the effects of therapeutic hypothermia on CYP450-mediated drug metabolism in a pediatric clinical study evaluating phenytoin elimination and to pre-clinically investigate the effects of hypothermia on drug transport via the ATP-binding cassette drug transporter pathways. Specifically, therapeutic hypothermia led to an overall decrease in the metabolism of phenytoin by reducing the maximum velocity of the enzymatic reaction. Furthermore, therapeutic hypothermia led to a decrease in the active drug transport of three ATP-Binding Cassette transporters (ABC), which play a significant role in the transport of drugs in various tissues throughout the body. Specifically, hypothermia to 33C led to a decrease of ABCB1, ABCG2, and ABCC1 by 28, 32, and 26% in permeability flux assays in MDCKII overexpressed-cells. Collectively, this work demonstrates that therapeutic hypothermia decreases drug metabolism in pediatrics following cardiac arrest. Further, it provides evidence of a decrease in ABC drug transport activity in vitro. Future research should investigate the effect of therapeutic hypothermia on drug transport activity in clinical studies. Additionally, studies should investigate the effects of therapeutic hypothermia versus injury/disease on drug pharmacokinetics in order to optimize the therapeutic benefits of medications by customizing dosing based on disease and therapeutic intervention in these critically ill patients.