RESEARCH OF THE MECHANISM OF MULTIPLE ORGAN FAILURE ASSOCIATED WITH SEPSIS-IN ASSOCIATION WITH APOPTOSIS

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Research in 1999 and 2000 : Pharmacokinetics of various drugs is affected by the development of sepsis, Propofol is an intravenous anesthetic used for sedation in patients with sepsis. To elucidate the alternation of pharmacokinetics of anesthetics by sepsis, we have elucidated the hepatic enzymes involved in the metabolism of propofol. We have shown that cytochrome P4502B6, not P4502C as previously reported, is the predominant P450 isoform involved in the metabolism of propofol using human liver microsomes, cDNA-expressed microsomes and monoclonal antibodies. Secondly, involvement of P4502B6 and P4502C in the metabolism of midazolam was examined since the pharmacokinetics of midazolam is inhibited by propofol, which was metabolized by P4502B6. Although the metabolism of midazolam was competitively inhibited by propofol both in vitro and in vivo, only P4503A4 was involved in the metabolism of midazolam to 1 '-hydroxy midazolam and P4502B6 or P4502C were not involved.Research in 2001 : To elucidate the pharmacokinetics of intravenous anesthetics in various conditions, we have established an animal model with Sprague-Dawley rats. This is an awake rat model with intraarterial and intravenous catheters, which enables to observe the effect of anesthetics with monitoring arterial pressure, blood gas tension. Sepsis model can be easily made by injecting lipopolysaccharide to this rat.Future plan : To elucidate the effect of sepsis on the levels of P4503A4mRNA in lymphocytes in peripheral blood, hepatic P4503A4 activity and apoptosis of the hepatic cells. The level of P4503A4mRNA in lymphocytes in peripheral blood is correlated with the P4503A4 activity in the liver. By comparing the level of P4503A4mRNA in lymphocytes in peripheral blood and the P4503A4 activity in the liver with the development of sepsis, we can detect whether apoptosis in the liver is induced by alteration in the P450 levels in the liver or P450 in the peripheral blood.