Drug-Drug Interactions With a Pharmacokinetic Basis

Abstract

The consequences of drug-drug interactions (DDIs) are multifaceted and altered pharmacokinetics can cause major concern to safety and efficacy. Metabolism-based DDIs are certainly the most prevalent, followed by absorption-based DDIs. The inhibition or induction of drug-metabolizing enzymes, most commonly cytochrome P450 (CYP) enzymes, are frequently associated with changes in drug clearance. Perpetrators can act as reversible inhibitors, inducers, and/or time-dependent inhibitors to impact the victim's affinity to CYP enzymes, efficacy, or both. Mathematical equations are used to quantitatively assess the area under the curve ratio of the victim administered with the perpetrator to the victim dosed alone. Observed to a lesser degree than metabolism-based DDIs, absorption-based interactions of orally administered compounds result in alterations to drug absorption and bioavailability. Acid-reducing agents are predominately associated with these DDIs as they influence a decrease in solubilized drug concentration and thereby reduce the drug concentration that permeates the gastrointestinal wall. Lastly, plasma proteins and transporters may be related to DDIs; however, there is typically a lack of pharmacokinetic consequence when there are changes in plasma protein binding and transporter activity. This chapter highlights the various pathways through which interactions can occur and how each will influence a victim's pharmacokinetics in combinatorial drug therapy.