PURPOSE: Hemorrhagic shock consequent to trauma and accidents is common in the clinical setting and its effect on cytochrome-P450 (CYP) mediated drug metabolism is largely unknown. We evaluated metabolic function of CYP isozymes by profiling the pharmacokinetics of 3 selective probe drugs in pigs during healthy and shocked states.
METHODS: Four Dorac pigs were intravenously administered CYP isozyme probes (dextromethorphan for CYP2D6, flurbiprofen for CYP2C9 and midazolam for CYP3A4 at doses of 0.5, 0.25 and 0.5 mg/kg respectively). Seven days later, hemorrhagic shock was induced in the pigs and the probe “cocktail” was administered following a 14 hour resuscitation phase. Blood samples were collected in both phases up to 48 hours. After LC-MS/Fl analysis, pharmacokinetic parameters were calculated and healthy and shock states were compared with a two-tailed, paired Student's t-test.
RESULTS: Hemorrhagic shock (post-resuscitation) appears to decrease the clearance of flurbiprofen (p =0.08) but inconsistent changes in clearance of dextromethorphan and midazolam were observed. Pigs in the post-hemorrhagic shock state had higher exposure to dextrorphan (metabolite of dextromethorphan; p =0.06), flurbiprofen (p <0.05), 4′-OH-flurbiprofen (metabolite of flurbiprofen; p =0.09) and 1′-OH-midazolam (metabolite of midazolam; p =0.13). The decreased clearance of flurbiprofen and higher exposure of dextrorphan and 4′-OH-flurbiprofen could be influenced by the effect of shock on renal clearance. The average half-lives increased from the healthy to shock states for dextromethorphan (45 vs 65 min), flurbiprofen (77 vs 108 min) and midazolam (54 vs 65 min).
CONCLUSION: Hemorrhagic shock followed by resuscitation had an inconsistent effect on CYP-mediated drug metabolism. Intra-subject variability was high and the effect of the hemorrhagic shock state on blood flow and renal clearance may have played a substantial role in the observed results.
CLINICAL IMPLICATIONS: Patients resuscitated from hemorrhagic shock and exposed to drugs metabolized by CYP-isozymes may have significant decreases in drug clearance and an increase in exposure to the drug metabolites. Predicting which patients will be affected is not possible at this time.
DISCLOSURE: Atul Kumar, No Financial Disclosure Information; No Product/Research Disclosure Information