Date of Award

1998

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Clinton Chichester

Abstract

Septic shock is the body's inflammatory response to an infection, and is usually associated with gram negative bacteria. It is characterized by hypotension and hypoperfusion, despite adequate fluid resuscitation, and can lead to multiple organ failure. At these advanced stages there is a high morbidity and mortality rate associated with it. One mediator of this inflammatory response is a lipopolysaccharide (LPS), or endotoxin, found in the gram negative bacterial cell wall. Besides having effects on the body as a whole, there are many cellular processes affected by endotoxin. In the body, there is a family of enzymes, the cytochrome P450 enzymes, which are the body's drug metabolizing enzymes. Although found in all tissue types, the P450 enzymes are mainly located in the liver. There are many families and isoforms of these enzymes, of which several are inhibited by endotoxin. The regulation of the P450 enzymes is very complex. During the systemic inflammatory response to endotoxin, many cytokine mediators are released into the bloodstream. These mediators, specifically tumor necrosis factor-a, interleukin-I , and interleukin-6, all are capable of regulating the activity, and production of the P450 enzyme system. Lidocaine is a widely used antiarrhythmic drug, which is metabolized by cytochrome P450 enzymes, to its major metabolite monoethylglycinexylidide (MEGX). Lidocaine is metabolized specifically by P450 3A2, 2Cl 1, and 2B 1 in the rat. The conversion of lidocaine to MEGX has been looked at as a method of evaluating liver function or dysfunction in a variety of liver related diseases, including viral hepatitis, cirrhosis, liver transplantation, and hypovolemic shock. This present study was undertaken to determine whether the conversion of lidocaine to MEGX was inhibited in vivo, in rats given a lethal dose of endotoxin. It was hoped that the degree of drug metabolizing inhibition could be determined using this whole animal model, since many of the systemic effects of septic shock, i.e. hypotension, also factor into the clearance of a high extraction compound, like lidocaine. Results from this study could potentially be helpful in determining drug metabolizing alterations in humans experiencing septic shock.

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