THE ROLE OF DRUG METABOLISM IN GENE THERAPY
An important aspect of pre-clinical drug development is evaluation of how a novel compound will influence drug metabolizing enzymes. In vitro, in vivo and clinical observations have documented that infection and inflammation significantly reduces the expression and function of cytochrome P450 (CYP) enzymes (Carcillo, 2003; Aitken, 2006). Understanding the effects of viral and non-viral vectors on CYP and other drug metabolizing enzymes is important since traditional drug regimens are also included in many gene therapy trials. Although this is a new concept in the gene therapy, it has been reported that a single dose of recombinant adenovirus suppresses rat CYP3A2 for 14 days without resolution (Callahan,2005). CYP3A2 is homologous to human CYP3A4, responsible for the metabolism of approximately 50% of marketed medications. Further study of other gene transfer vectors would be useful to identify potential drug interactions, adverse reactions and clinical fail-ures that may occur during gene therapy clinical trials. This is also of importance since some gene transfer applications rely on metabolism of a medic-inal substance to regulate expression of the transgene (see below) while others focus on over-expression of drug metabolizing enzymes to improve the effect of some medicinal compounds.
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