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

Abstract

ABSTRACT:Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for individuals experiencing cardiac arrest (CA); however, its effects combined with disease pathogenesis on drug disposition and response have not been fully elucidated. We determined the activities of four major hepatic-metabolizing enzymes (CYP3A, CYP2C, CYP2D, and CYP2E) during hypothermia after experimental CA in rats by evaluating the pharmacokinetics of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), CA normothermia, sham hypothermia (32.5-33°C), and CA hypothermia groups. Probe drugs (midazolam, diclofenac, dextromethorphan, and chlorzoxazone) were given simultaneously by intravenous bolus after temperature stabilization. Multiple blood samples were collected between 0 and 8 h after drug administration. Pharmacokinetic (PK) analysis was conducted using a noncompartmental approach and population PK modeling. Noncompartmental analysis showed that the clearance of midazolam (CYP3A) in CA hypothermia was reduced from sham normothermia rats (681.6 ؎ 190.0 versus 1268.8 ؎ 348.9 ml ⅐ h ؊1 ⅐ kg ؊1 , p < 0.05). The clearance of chlorzoxazone (CYP2E) in CA hypothermia was also reduced from sham normothermia rats (229.6 ؎ 75.6 versus 561.89 ؎ 215.9 ml ⅐ h ؊1 ⅐ kg ؊1 , p < 0.05). Population PK analysis further demonstrated the decreased clearance of midazolam (CYP3A) was associated with CA injury (p < 0.05). The decreased clearance of chlorzoxazone (CYP2E1) was also associated with CA injury (p < 0.01). Hypothermia was found to be associated with the decreased volume of distribution of midazolam (V 1 ), dextromethorphan (V 1 ), and peripheral compartment for chlorzoxazone (V 2 ) (p < 0.05, p < 0.05, and p < 0.01, respectively). Our data indicate that hypothermia, CA, and their interaction alter cytochrome P450-isoform specific activities in an isoform-specific manner.

Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction

“…In contrast, in the prasugrel and ticagrelor subgroups non-effective PRI values were always associated with massive return from the NGT (800-900 mL/24 h), and thus their absorption was probably significantly reduced or limited. The impact of slightly altered liver function in our patients may also have contributed to the reduced efficacy of clopidogrel, because the reduced metabolic activity of CYP isoforms involved in the conversion of clopidogrel into its active metabolite during TH has already been described [22]. In our view, the efficacy of prasugrel and ticagrelor is not affected by these liver metabolic changes.…”

The influence of hypothermia on the management of traumatic cardiac arrest

“…Therefore, hypothermia is associated with reductions in drug absorption, metabolism, tubular secretion and reabsorption 8. These effects can subsequently lead to reduced drug clearance and smaller volumes of distribution 9. Conversely, passive processes of filtration and drug-protein binding are not significantly altered by hypothermia 8…”

The Impact of Extracorporeal Life Support and Hypothermia on Drug Disposition in Critically Ill Infants and Children

“…146,147 In healthy adult volunteers, midazolam Cl but not Vd was affected by induced mild hypothermia. 113 In an adult population with traumatic brain injury with mild hypothermia (32–34°C), midazolam concentrations increased 5-fold during hypothermia, with a subsequent decrease in plasma levels during rewarming.…”