Chapter 15 - Cytochrome P450 Inhibition

Abstract

Many patients receive more than one drug at a time, and physicians must be careful to avoid drug–drug interactions (DDI). DDI is the interference of one drug with the normal metabolic or pharmacokinetic behavior of a coadministered drug. A major DDI concern is cytochrome P450 (CYP) inhibition. CYP inhibition has caused withdrawal from clinical use or restricted use of some major drugs. Because of its effects on clearance and half-life, CYP inhibition has become an important concern with the Food and Drug Administration (FDA) and at pharmaceutical companies. CYP inhibition now is assessed for a lead series from the earliest stages of the discovery project and can cause a lead series to be diminished in priority if the issue is uncorrectable. Medicinal chemists often can modify the structure to reduce CYP inhibition. Pharmaceutical companies must test each clinical candidate for its potential to inhibit CYP isozymes. Data on CYP inhibition is included in regulatory submissions to the FDA. Strong DDI potential can greatly affect the marketability of the drug. It is good for a new clinical candidate to be metabolized by multiple CYP isozymes, to reduce its potential metabolic inhibition by another drug.