When Does the Rate-Determining Step in the Hepatic Clearance of a Drug Switch from Sinusoidal Uptake to All Hepatobiliary Clearances? Implications for Predicting Drug-Drug Interactions.

For dual transporter-enzyme substrate drugs, the extended clearance model 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 (CLs in), even if the drug is eliminated mainly 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 enzymes; however, this is true only if the condition required to maintain CLs 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 CLs in to all hepatobiliary clearances [i.e., metabolic/biliary clearance (CLmet + bile) and CLs in], leading to unexpected systemic DDIs, such as metabolic DDIs, when only transporter DDIs were anticipated. As expected, these analyses revealed that the RDS switch depends on the ratio of CLmet + bile to sinusoidal efflux clearance (CLs ef). Additional analyses revealed that for intravenously administered drugs, the RDS switch also depends on the magnitude of CLs in We analyzed published in vitro quantified hepatobiliary clearances and observed that most drugs have a CLmet + bile/CLs ef ratio < 4; hence, in practice, the magnitude of CLs 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.