Introduction Therapeutic hypothermia is being employed, clinically based, on its neuro-protective benefits. Both critical illness and therapeutic hypothermia significantly affect drug disposition, potentially contributing to drug-therapy and drug-disease interaction. Currently, there is limited written information of the known alterations in drug concentration and response during mild hypothermia treatment and there is a limited understanding of the specific mechanisms that underlie alterations in drug concentrations and the potential clinical importance of these changes. Areas covered A systemic review of the effect of therapeutic hypothermia on drug metabolism, disposition, and response is provided. Specifically, the clinical and preclinical evidence of the effects of therapeutic hypothermia on blood flow, specific hepatic metabolism pathways, transporter, renal excretion, pharmacodynamics and rewarming effect are reviewed. Expert Opinion Available evidence demonstrates that mild hypothermia decreases the clearance of a variety of drugs with apparently little change in drug protein binding. Recent evidence suggests that the magnitude of the change is elimination route specific. Further research is needed to determine the impact of these alterations on both drug concentration and response in order to optimize the hypothermia therapy in this vulnerable patient population.

ABSTRACT:The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4°C saline infusions and 4°C saline ؉ magnesium) and two normothermia groups (37°C saline infusions and 37°C saline ؉ magnesium). The lowest temperatures achieved in the 4°C saline ؉ magnesium and 4°C saline infusions were 35.4 ؎ 0.4 and 35.8 ؎ 0.3°C, respectively. A significant decrease in the formation clearance of the major metabolite 1-hydroxymidazolam was observed during the 4°C saline ؉ magnesium compared with that in the 37°C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5°C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

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.

Aim: To study the in vivo and in vitro metabolism and the effect of para-toluenesulfonamide (PTS) on cytochrome P450 enzymes (CYP450). Methods: Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. Results: The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66±0.17 and 0.60±0.12 nmol/mg. The K m and V max were 92.2 µmol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. Conclusion: Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.