Abstract
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 (CYP). It was reported that when organ preserving solutions are exposed to carbon monoxide (CO), the treatment was effective in suppressing the post-reperfusion reduction in renal CYP 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 CYP during a massive hemorrhage compared to plasma expanders and RBC resuscitation. To achieve this, we created 40% hemorrhagic-shock model rats followed by resuscitation using recombinant human serum albumin, RBC and CO-RBC. At 1 hr after resuscitation, the expressions of hepatic CYP isoforms (1A2, 2C11, 2E1, 3A2) were significantly decreased in the RBC resuscitation group compared to the sham group. Such alterations in hepatic CYP significantly resulted in an increase in the plasma concentrations of substrate drugs (caffeine (1A2), tolbutamide (2C11), chlorzoxazone (2E1) and midazolam (3A2)) for each CYP isoform and, hence, the hypnotic action of midazolam could be significantly prolonged. Interestingly, the reductions in hepatic CYP 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.
- Received September 6, 2012.
- Accepted October 15, 2012.
- The American Society for Pharmacology and Experimental Therapeutics