Chapter 15 - Cytochrome P450 Inhibition

Abstract

Drug-drug interaction due to cytochrome P450 (CYP) inhibition occurs if two drugs are co-administered and the second drug inhibits normal P450 metabolism of the first drug. The result is that clearance of the first drug is lower than that when dosed alone, thus increasing its Cmax, area under the curve, and t1/2. The concentration of the first drug might exceed its toxic concentration and cause negative health effects. The second (inhibiting) drug is termed the “perpetrator” and the first drug is termed the “victim.” Perpetrator inhibition of CYP can be reversible or irreversible. Irreversible inhibition inactivates the enzyme and the activity is diminished until new enzymes are generated through de novo synthesis. The terms mechanism-based inhibition or time-dependent inhibition are used for irreversible inhibition. If a drug candidate that has in vitro CYP inhibition and it is predicted to be clinically relevant at the efficacious dose, additional clinical CYP inhibition studies are performed. If CYP inhibition is observed in human trials, restrictive labeling is included in the product package insert on co-medication. Several useful synthetic strategies have been developed to reduce the CYP inhibition of a lead series.