PT  - JOURNAL ARTICLE
AU  - Gabriela I Patilea-Vrana
AU  - Jashvant 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 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.081307
4099  - http://dmd.aspetjournals.org/content/early/2018/08/16/dmd.118.081307.short
4100  - http://dmd.aspetjournals.org/content/early/2018/08/16/dmd.118.081307.full
AB  - 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 (CLsin), 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 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] as well as CLsin) 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 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 CLmet+bile/CLsef ratio < 4, and 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.