PT - JOURNAL ARTICLE AU - Gabriela I. Patilea-Vrana AU - Jashvant D. Unadkat TI - 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 AID - 10.1124/dmd.118.081307 DP - 2018 Nov 01 TA - Drug Metabolism and Disposition PG - 1487--1496 VI - 46 IP - 11 4099 - http://dmd.aspetjournals.org/content/46/11/1487.short 4100 - http://dmd.aspetjournals.org/content/46/11/1487.full SO - Drug Metab Dispos2018 Nov 01; 46 AB - 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 (CLsin), 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 CLsin 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 CLsin to all hepatobiliary clearances [i.e., metabolic/biliary clearance (CLmet + bile) and CLsin], 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 (CLsef). Additional analyses revealed that for intravenously administered drugs, the RDS switch also depends on the magnitude of CLsin. We analyzed published in vitro quantified hepatobiliary clearances and observed that most drugs have a CLmet + bile/CLsef ratio < 4; hence, in practice, the magnitude of CLsin 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.