Date of Defense

Summer 7-18-1997

Department

Biological Sciences

First Advisor

William Jackson, Biological Sciences

Second Advisor

Richard Voorman, Pharmacia & Upjohn Incorporated

Abstract

Delavirdine, an HIV-1 reverse transcriptase inhibitor, was recently approved for use as an HIV/AIDS therapeutic. Delavirdine is a BHAP derivative of a nonnucleoside type reverse transcriptase inhibitor. Compared to the nucleoside analog, there have been fewer reported side effects, in both frequency and severity, than with drugs such as AZT. Cytochrome P450 3A4 has previously been demonstrated to be the major enzyme involved in the catalysis of delavirdine to desalkyl delavirdine through N-dealkylation pathways. CYP3A4 metabolizes delavirdine, but as the concentration of delavirdine is increased, CYP3A4 demonstrates auto-inhibition. Approximately 75% of delavirdine metabolism has been shown to be inhibited, while the other 25% has not been accounted for. The present study examined various isoforms of the P450 enzyme system responsible for metabolizing delavirdine to determine what, if any, additional enzymes contribute to delavirdine clearance. CYP3A4, CYP2D6, CYP3A5, CYP2C8, and CYP2C18 were all shown to catalyze the metabolism of delavirdine to desalkyl delavirding by N-dealkylation. It is possible that these enzymes may be responsible for aiding in delavirdine clearance.

Access Setting

Honors Thesis-Campus Only

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