Moderate hypothermia prevents cardiac arrest-mediated suppression of drug metabolism and induction of interleukin-6 in rats*

Abstract

Objective Therapeutic hypothermia is being clinically employed to reduce neurological deficits after cardiac arrest (CA). Patients receiving hypothermia after CA receive a wide-array of medications. During hypothermia, drug metabolism is markedly reduced. Little, however, is known about the impact of hypothermia on drug metabolism after re-warming. The objective of this study was to examine the effect of CA and hypothermia on the functional regulation of two major drug metabolizing cytochrome P450 (CYP) isoforms. Design Laboratory investigation. Setting University pharmacy school and animal research facility. Subjects Thirty-six male Sprague-Dawley rats. Interventions Hypothermia was induced via surface cooling in a rat CA model and maintained for 3h. Animals were sacrificed at 5 or 24h and liver was analyzed for hepatic activity and mRNA expression of CYP3A2 and CYP2E1. Plasma interleukin-6 (IL-6) concentrations were determined. The effect of IL-6 on PXR mediated transcription of the rat CYP3A2 promoter was evaluated via luciferace reporter in HepG2 cells. Measurements and Main Results At 24h after CA a decrease in CYP3A2 and CYP2E1 activity was observed, 55.7±12.8% and 46.8±29.7% of control, respectively (p<0.01). CA decreased CYP3A2 mRNA(p<0.05), but not CYP2E1 mRNA. Expression of other PXR target enzymes and transporter genes were similarly down-regulated. CA also produced a ∼10-fold increase in plasma IL-6. CA mediated inhibition of CYP3A2 and CYP2E1 was attenuated by hypothermia, as was the increase in IL-6. Furthermore, IL-6 attenuated PXR-mediated transcription of the CYP3A2 promoter. Conclusions CA produces CYP3A2 down-regulation at 24h, potentially via IL-6 effects on PXR-mediated transcription. Also, hypothermia attenuates the CA mediated down-regulation, thereby normalizing drug metabolism after re-warming.

Mild hypothermia decreases fentanyl and midazolam steady-state clearance in a rat model of cardiac arrest

“…Groups were well-matched on weight, resuscitation time, and total bicarbonate replacement (Table 1). The mean PaO 2 over the 8-10 h study period was higher in the hypothermia group after the CA (p < 0.05) as expected(11, 17). Hourly mean arterial pressure, pH, PaCO 2 , oxygen saturation, blood bicarbonate, lactate, glucose, hematocrit, lactate, and base deficit were not different between groups.…”

“…In order to mimic the clinical application of hypothermia we incorporated specific design elements into our CA and hypothermia protocols. In previous work, short duration (3 h), low temperature (30°C) hypothermia, and intravenous bolus of probes of CYP pathways were used in proof-of-concept studies to show that cooling could alter drug metabolism post CA(11, 17). In this study, we delayed the initiation of hypothermia for 1 h post ROSC, targeted a temperature of 33°C to match the now standard goal range of 32-34°C, and extended the duration of hypothermia to 8-10 h. Similarly, we selected the commonly used drugs, fentanyl and midazolam, at a dosing regimen that produced blood concentrations similar to those achieved in patients.…”

“…CA was induced as previously described(16, 17) with modifications for a prolonged time period of temperature management, and steady-state pharmacokinetic studies. Rats were anesthetized with 4% isoflurane via nose cone, endotracheally intubated, and mechanically ventilated to maintain a pCO 2 of 35-45mmHg.…”

Cardiac Arrest and Therapeutic Hypothermia Decrease Isoform-Specific Cytochrome P450 Drug Metabolism

“…Hypothermia reduced the peripheral volume of distribution. This result is consistent with a previous study in our laboratory, in which no significant difference was observed between CA normothermia and CA hypothermia at 33°C for chlorzoxazone metabolism with a 5-hour hypothermia treatment (Tortorici et al, 2009). Twenty-four hours after CA and rewarming, the activity of CYP2E1 in the CA normothermia group was found to be significantly lower than that in the control and CA hypothermia groups.…”

Politics and Hypothermia—What Might They Have in Common? Editorial Comment on Silasi and Colbourne, 2011

“…Similarly, hypotension during its application was seen in other RCTs of moderate hypothermia in adult TBI, as reported by Clifton et al (2001). Mild systemic hypothermia is also well known to have inhibitory effects on cytochrome P450-mediated drug metabolism that may predispose patients to toxicity and complications (Tortorici et al, 2006(Tortorici et al, , 2007(Tortorici et al, , 2009Hostler et al, 2010), and inhibit leukocyte migration, which may increase the risk of infections such as pneumonia (Whalen et al, 1997;Ishikawa et al, 1999). Obviating these problems, particularly in the setting of TBI and stroke might be critical to its successful use-where RCTs have yet to be designed such that whole body cooling can demonstrate benefit.…”