Reproducibility of the In Vivo Effect of the Selective Serotonin Reuptake Inhibitors on the In Vivo Function of Cytochrome P450 2D6: An update (Part II)

摘要

This column is the second in a two-part series explaining how the effects of drugs on human drug metabolizing enzymes such as cytochrome P450 (GYP) 2D6 are studied and quantified. A considerable amount of research has focused on the fact that some drugs-including some antidepressants-are capable of producing substantial inhibition of one or more human drug metabolizing enzymes under usual dosing conditions. This work has demonstrated that drugs within the same therapeutic class and even the same phar-macodynamic class can have substantial and clinically meaningful differences in their -effects on such enzymes and that such differences can be important in choosing among members of a therapeutic class.The importance of such enzyme inhibition has been discussed in earlier columns.One column pointed out that screening for such unintended effects on human drug metabolizing enzymes is now part of the earliest testing of new candidate drugs and that the results of such tests are used to make "Go, No Go" decisions about which drugs to take forward into human testing.Another column pointed out that substantial unintended inhibition of such enzymes has resulted in the withdrawal of a number of drugs from the U.S. market over the past decade.These withdrawals occurred when it was recognized that the co-administration of these drugs sets the stage for serious and even fatal drug-drug interactions when the inhibitor drug ("perpetrator") is used in combination with a substrate drug ("victim") that has a narrow therapeutic index and is predominantly metabolized by the inhibited enzyme.