Dynamic Simulations with the DDI Module

Dynamic simulations using the DDI module account for changes in metabolism and carrier-mediated transport in the gut, liver, and other tissues. These tissues are identified with the assistance of a PBPK model, focusing on where metabolism occurs or where distribution relies on carrier-mediated transport of the interacting drugs (victim and perpetrator) and their associated metabolic pathway compounds. If the same enzyme or transporter affects multiple compounds in the system, then GastroPlus® automatically considers their competition for binding sites on the enzyme or transporter.

In dynamic simulations, the unbound concentration at the site of metabolism or transport determines the unbound concentration.

Equation 4-14 through Equation 4-16 detail the equations used for dynamic simulations in the DDI module.

Equation 4-14 shows the calculation for the effect of a competitive inhibitor on the metabolic rate of the victim or the carrier-mediated transport by a specific enzyme or transporter. This effect is accounted for by adjusting the K_m value for the victim.

Equation 4-14: Effect of a competitive inhibitor on the metabolic rate of the victim or the carrier-mediated transport by a specific enzyme or transporter

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Equation 4-15 and Equation 4-16 show the effect of competitive inhibitor, time-dependent inhibitor (TDI), and inducer on the metabolic rate of the victim or the carrier-mediated transport of a specific enzyme or transporter. This effect is accounted for by changing the protein (enzyme or transporter) activity and by adjusting the K_m value for the victim to account for the competitive aspect of the interaction.

Equation 4-15: Effect of a competitive inhibitor and time-dependent inhibitor or inducer on the victim of the carrier-mediated transport of a specific enzyme or transporter

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Equation 4-16: Effect of a competitive time-dependent inhibitor (TDI) or inducer on the activity of affected enzyme or transporter

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where:

Variable	Definition
We don't have a way to export this macro.	The metabolic rate of the victim or carrier-mediated transport
We don't have a way to export this macro.	The i^th inhibitor or inducer.
We don't have a way to export this macro.	The j^th competitor.
We don't have a way to export this macro.	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.
We don't have a way to export this macro.	The protein (enzyme or transporter) activity (expression level) in a given tissue at a given time.
We don't have a way to export this macro.	The maximum velocity of the enzyme or transporter.
We don't have a way to export this macro.	The concentration of the unbound substrate (victim) at the binding site.
We don't have a way to export this macro.	The Michaelis-Menten constant of the enzyme or transporter.
We don't have a way to export this macro.	The concentration of unbound substrate.
We don't have a way to export this macro.	The concentration of unbound inhibitor or inducer at the binding site.
We don't have a way to export this macro.	The inactivation constant of a perpetrator against individual enzymes or transporters that are involved in the metabolism or transport of the victim.
We don't have a way to export this macro.	The maximum induction potential of a perpetrator against individual enzymes or transporters that are involved in the metabolism of the victim.
We don't have a way to export this macro.	The turnover rate of an individual enzyme or transporter.
We don't have a way to export this macro.	The inhibition constant of the inhibitor for a given enzyme or transporter.
We don't have a way to export this macro.	The induction constant of a perpetrator against individual enzymes or transporters that are involved in the metabolism or transport of the victim.
We don't have a way to export this macro.	The number of multiple substrates of given enzyme/transporter.
We don't have a way to export this macro.	The number of multiple competitive inhibitors of given enzyme/transporter.