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

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

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

where:

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.