ArticleDrug metabolism and disposition: the biological fate of chemicals2011
Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 34 citations in OpenAlex.
- Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.Critical care medicine · 2013Trial
- Cardio-Oncology in Cold Climates: Epidemiological Features, Bidirectional Interaction Mechanisms, and Integrated Management Strategies.Cardiovascular toxicology · 2026Review
- Adverse drug reactions in therapeutic hypothermia after cardiac arrest.Therapeutic advances in drug safety · 2017Article
- Variability of Post-Cardiac Arrest Care Practices Among Cardiac Arrest Centers: United States and South Korean Dual Network Survey of Emergency Physician Research Principal Investigators.Therapeutic hypothermia and temperature management · 2017Article
- Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations.Therapeutic hypothermia and temperature management · 2016Review
- Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction.Journal of thrombosis and thrombolysis · 2016Observational
- Hypothermia after cardiac arrest as a novel approach to increase survival in cardiopulmonary cerebral resuscitation: a review.Iranian Red Crescent medical journal · 2014Review
- Brain temperature and its fundamental properties: a review for clinical neuroscientists.Frontiers in neuroscience · 2014Review
- Drug dosing during hypothermia: to adjust, or not to adjust, that is the question.Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies · 2013Article
- The impact of extracorporeal life support and hypothermia on drug disposition in critically ill infants and children.Pediatric clinics of North America · 2012Article
- Predicting Survival with Good Neurological Outcome Within 24 Hours Following Out of Hospital Cardiac Arrest:The Application and Validation of a Novel Clinical Score.Journal of neurology & translational neuroscienceArticle
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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 · h(-1) · 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 · h(-1) · 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.
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