Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

Abstract

Abstract. Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs

“…We have shown that the primary elimination route can be well predicted using in vitro permeability rates to predict the extent of metabolism, segregating classes 1 and 2 from 3 and 4, while two computed molecular features of a drug, metabolic stability and polarizability, can then predict if a poorly metabolized drug is eliminated in the bile or the urine as unchanged drug (26,27). These predictions may be very valuable during drug discovery and development.…”

“…We therefore were able to classify drugs into their primary elimination route: extensive metabolism, renal elimination as parent drug, or biliary elimination as parent drug. As a result, we were able to develop a system of predicting the major elimination route using in vitro permeability rate measurements to predict the extent of metabolism followed by a two-feature logistic regression model including calculated metabolic stability and polarizability that predicts when a poorly permeable, orally administered drug is likely to be eliminated primarily as unchanged drug in the bile or primarily as unchanged drug in the urine (27).…”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…Deriving biliary organoids will allow for an in vitro human model of the drug secretion system and biliary gland diseases. [102][103][104][105] For new and current drugs, it is crucial to understand the process of elimination through the biliary gland, which could help facilitate drug development and design, [106,107] and the biliary organoids could provide a system to model this process. In addition to drug secretion, biliary gland organoids derived from iPSC lines can model genetic diseases such as cystic fibrosis (CF) where the cystic fibrosis transmembrane conductance regulator (CFTR) is impaired and disrupts fluid secretion within the glands.…”

Effect of OATP-binding on the prediction of biliary excretion

“…Quantitative prediction of biliary excretion of compounds has been investigated in several recent publications employing various QSAR techniques (Chen et al 2010, Luo et al, 2010Yang et al, 2009, Sharifi andGhafourian, 2014;Hosey et al, 2014). It is believed that the development of a reliable structure-activity model for the prediction of cholephilic compounds is not an easy task (Gandhi and Morris, 2012;Hosey et al, 2014).…”

“…It is believed that the development of a reliable structure-activity model for the prediction of cholephilic compounds is not an easy task (Gandhi and Morris, 2012;Hosey et al, 2014). One explanation for the complexity of structure-activity rationalisation and quantitative prediction of biliary excretion may be the different structural requirements for different transport proteins that are involved in the biliary excretion.…”