Abstract

For dual transporter/enzyme substrate drugs, the extended clearance model (ECM) can be used to predict the rate-determining step(s) (RDS) of a drug and hence predict its drug-drug interaction (DDI) liabilities (i.e. transport, metabolism, or both). If the RDS of the hepatic clearance of the drug is sinusoidal uptake clearance (CL^s_in), even if the drug is mainly eliminated by hepatic metabolism, its DDI liability (as viewed from changes to systemic drug concentrations) is expected to be inhibition or induction of uptake transporters but not hepatic metabolic enzymes. However, this is true only if the condition required to maintain CL^s_in as the RDS is maintained. Here, we illustrate through theoretical simulations that the RDS condition may be violated in the presence of a DDI. That is, the RDS of a drug can switch from CL^s_in to all hepatobiliary clearances (i.e. metabolic/biliary clearance [CL_met+bile] as well as CL^s_in) leading to unexpected systemic DDI's, such as metabolic DDI's when only transporter DDI's are anticipated. As expected, these analyses revealed that the RDS switch depends on the ratio of CL_met+bile to sinusoidal efflux clearance (CL^s_ef). Additional analyses revealed that for intravenously administered drugs, the RDS switch also depends on the magnitude of CL^s_in. We analyzed published in vitro quantified hepatobiliary clearances and observed that most drugs have CL_met+bile/CL^s_ef ratio < 4, and hence in practice, the magnitude of CL^s_in must be considered when establishing the RDS. These analyses provide insights, previously not appreciated, and a theoretical framework to predict DDI liabilities for drugs that are dual transporter/enzyme substrates.