Drug-Drug Interaction Module Equations

Variable

Definition

The measure of the total exposure of the drug to the body with oral dosage when co-dosed with an inhibitor/inducer.

The measure of the total exposure of the drug to the body with oral dosage.

The fraction of the drug that bypasses gut metabolism.

The contributions of individual enzymes (E) to the victim drug’s gut and liver (or systemic) clearance, respectively.

The fraction of the victim drug’s gut and liver (or systemic) clearance due to mechanisms not affected by a perpetrator, respectively.

The effective perpetrator gut concentration and the effective perpetrator liver (or systemic) concentration, respectively.

The reversible (competitive) inhibition constant, the irreversible inhibition constant, and the induction constant, respectively, of a perpetrator against individual enzymes that are involved in the victim’s gut metabolism, liver metabolism, or both.

The inactivation constant and the maximum induction potential, respectively, of a perpetrator against individual enzymes that are involved in the victim’s gut metabolism, liver metabolism, or both.

The turnover rate of individual enzymes, with different turnover rates specified for the gut and liver, respectively.

Variable

Definition

The dose of the drug.

The dosing interval.

The clearance rate of the drug dose.

The elimination rate constant.

The absorption rate constant.

The fraction of the dose that is absorbed.

The fraction of the dose that was absorbed in the portal vein.

The bioavailability of the drug dose.

The liver blood flow rate.

The enterocytic blood flow rate.

The percent of drug unbound in plasma.

Variable

Definition

The sum of the in vivo intrinsic clearances for all CYP enzymes.

The percent of the total systemic clearance that is due to non-metabolic pathways.

Variable

Definition

The in vitro intrinsic clearance measured with inhibitor.

The in vitro intrinsic clearance as measured in the presence of a specific inhibitor for a given CYP enzyme.

Variable

Definition

The sum of the in vivo intrinsic clearances for all CYP enzymes.

The percent of the total systemic clearance that is due to non-metabolic pathways.

Variable

Definition

The metabolic rate of the victim or carrier-mediated transport

The i^th inhibitor or inducer.

The j^th competitor.

The initial protein (enzyme or transporter) activity (expression level) in a given tissue, where initial means before the addition of the inhibitor. If the inhibitor is a competitive inhibitor, then this activity remains constant.

The protein (enzyme or transporter) activity (expression level) in a given tissue at a given time.

The maximum velocity of the enzyme or transporter.

The concentration of the unbound substrate (victim) at the binding site.

The Michaelis-Menten constant of the enzyme or transporter.

The concentration of unbound substrate.

The concentration of unbound inhibitor or inducer at the binding site.

The inactivation constant of a perpetrator against individual enzymes or transporters that are involved in the metabolism or transport of the victim.

The maximum induction potential of a perpetrator against individual enzymes or transporters that are involved in the metabolism of the victim.

The turnover rate of an individual enzyme or transporter.

The inhibition constant of the inhibitor for a given enzyme or transporter.

The induction constant of a perpetrator against individual enzymes or transporters that are involved in the metabolism or transport of the victim.

The number of multiple substrates of given enzyme/transporter.

The number of multiple competitive inhibitors of given enzyme/transporter.