Human Cytochromes P450 and Their Role in Metabolism-Based Drug-Drug Interactions
Cytochrome P450 (P450) binding is now widely recognized as a major focus for drug-drug interactions in the pharmaceutical industry. P450 metabolism-based drug-drug interactions, in vitro and in vivo, are now routinely part of the product labeling and advertising copy, often in incomprehensible detail. Although this focus has led, on more than one occasion, to undue emphasis on clinically insignificant effects, there does exist in many circumstances a significant risk to patients arising from interactions with the P450 enzyme system. What is more, these interactions can be reasonably well predicted from in vitro data and extrapolated from drug to drug, thanks to the large body of literature information. From the authors' survey of the available data on the elimination pathways for 438 drugs marketed in the United States and Europe, the overall importance of P450-mediated clearance can be determined. The elimination of unchanged drug via urine (the most commonly defined), bile, expired air, or feces represented, on average, approximately 25% of the total elimination of dose for these
compounds. P450-mediated metabolism represented 55%, with all other metabolic processes making up the remaining 20%. Thus, this focus (or perhaps obsessive compulsion) on studying P450 is justified.