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.