Red blood cell (RBC) transfusions for massive
hemorrhage induce systemic ischemic-reperfusion and influence the disposition and pharmacological activity of drugs as a result of a reduction in the level of expression and activity of
cytochrome P450s (P450). It was reported that, when organ-preserving solutions are exposed to
carbon monoxide (CO), the treatment was effective in suppressing the postreperfusion reduction in renal P450 levels in cases of
kidney transplantation. Therefore, we hypothesized that transfusions with RBC that contain bound CO (CO-RBC) would protect the hepatic level of rat P450 during a massive
hemorrhage, compared with plasma expanders and RBC
resuscitation. To achieve this, we created 40%
hemorrhagic-shock model rats, followed by
resuscitation, with use of recombinant
human serum albumin, RBCs, and CO-RBCs. At 1 hour after
resuscitation, the expressions of hepatic P450
isoforms (1A2, 2C11, 2E1, and 3A2) were significantly decreased in the RBC
resuscitation group, compared with the
sham group. Such alterations in hepatic P450 significantly resulted in an increase in the plasma concentrations of substrate drugs (
caffeine [1A2],
tolbutamide [2C11],
chlorzoxazone [2E1], and
midazolam [3A2]) for each P450
isoform, and thus, the
hypnotic action of
midazolam could be significantly prolonged. Of interest, the reductions in hepatic P450 activity observed in the RBC group were significantly suppressed by CO-RBC
resuscitation, and consequently, the pharmacokinetics of substrate drugs and the pharmacological action of
midazolam remained at levels similar to those under
sham conditions. These results indicate that CO-RBC
resuscitation has considerable potential in terms of achieving safe and useful
drug therapy during massive
hemorrhages.