Doctoral Dissertations

Sherry Cox

Date of Award

5-2003

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Joe Bartges

Abstract

Drugs are potentially toxic substances that elicit dosage-dependent therapeutic effects for specific disease conditions. The efficacy of a drug regimen depends on the concentration of the drug at the site of needed activity and the duration of time it is maintained. The selection of dosing regimens for different species requires the establishment of pharmacokinetic equivalency between species; that is, achieving equivalent peak serum and tissue concentrations and duration of drug exposure. Drug metabolism is a direct reflection of the multiple enzyme systems that characterize different species and is often the most important single factor in regulation if drug concentrations in the body. The largest concentration of enzymes catalyzing these reactions is located in the liver; however, significant concentrations also exist in other tissues such as the intestine. The cytochrome P450 system metabolizes the majority of drugs. Although cytochrome P450 enzymes exist in all species examined to date, minor changes in the structure or tissue distribution of the enzymes may lead to great differences in the metabolism and elimination of specific drugs. A lack of consideration of the rates of biotransformation and elimination of drugs in animals particularly those intended for food may result in drug residues, such as quinolones, in consumed meats. Alternatively, ineffective drug concentrations may prevent killing of bacteria, leading to contamination of meats. More important, low level antibiotic concentrations may favor development of resistant bacterial strains. In an effort to determine pharmacokinetic differences that can indirectly affect development of quinolone resistance in bacteria, differences in quinolone disposition will be identified by allometric analysis of pharmacokinetic data from different species will be analyzed. Activities of specific cytochrome P450 enzymes will be examined in swine.

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