Assessment of potential drug interactions by characterization of human drug metabolism pathways using non‐invasive bile sampling

Abstract

AIMCharacterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. METHODSixteen healthy, elderly subjects underwent non-invasive bile capture using a peroral string device (Entero-Test ® ) prior to and following a single oral dose of GSK1325756 (100 mg). The device was swallowed by each subject and once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth and bile samples were analyzed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. RESULTSNuclear magnetic resonance spectroscopy (NMR) indicated that the O-glucuronide metabolite was the major metabolite of GSK1325756, representing approximately 80% of drug-related material in bile. As bile is the major clearance route for GSK1325756 (only 4% of the administered dose was excreted in human urine), this result indicates that uridine 5'-diphospho-glucuronosyltransferases (UGTs) are the major drug metabolizing enzymes responsible for drug clearance. The relatively minor contribution made by oxidative routes reduces the concern of CYP-mediated victim drug interactions. CONCLUSIONThe results from this study demonstrate the utility of deploying the Entero-Test® in early human studies to provide information on the biliary disposition of drugs and their metabolites. This technique can be readily applied in early clinical development studies to provide information on the risk of interactions for drugs that are metabolized and eliminated in bile. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inhibition of a drug clearance mechanism by another co-administered drug can result in a victim drug interaction. Understanding the enzymes and transporters involved in the clearance of a drug, generally derived from in vitro systems, can help inform the drug interaction risk.• Knowledge of the drug and metabolite excretion profiles is required in human subjects to put mechanistic enzyme and transporter information into clinical context and this is generally limited to metabolic investigations of urine and faeces following a dose of radiolabelled drug during late clinical development. WHAT DOES THIS STUDY ADD?• This clinical study demonstrates that human bile samples collected for drug and metabolite analysis can be used to inform the risk of victim drug interactions for drugs in early clinical development.• Using non-invasive bile sampling technology the biliary disposition of GSK1325756, a drug being developed for the treatment of chronic obstructive pulmonary disease (COPD), was evaluated in healthy elderly subjects. This showed that an O-glucuronide was the major metabolite in bile, confirming that clearance of GSK1325756 is mediated predominately by UGT enzymes.• The relatively low levels of oxidative metabolites in human bile indicate a...

Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling

“…Indeed, Entero-Test-collected bile sample analysis confirmed that the glucuronide of GSK1322322 (M9) was the major biliary radiocomponent in humans. Although the Entero-Test, a noninvasive and easy-to-use device, has been used in human bile collections before (Vonk et al, 1986;Muraca et al, 1989;Bloomer et al, 2012), this is the first study, to our knowledge, that it has been successfully incorporated into a conventional human radiolabel study. Biliary metabolites have often been crucial in evaluating drug disposition, especially if the metabolites were unstable after biliary secretion into the gut.…”

“…Recently, GSK pioneered its use in metabolism studies. The device has proven useful in sampling bile from both dogs and human subjects in nonradiolabeled metabolism studies (Guiney et al, 2011;Bloomer et al, 2012), but it has never been tested in a conventional human radiolabel study where its application could be fully evaluated.…”

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

“…It is also possible to get qualitative information into metabolic pathways of orally administered drugs in bile with the use of recent techniques such as Entero-Test (Guiney et al, 2011;Bloomer et al, 2013), although this has not yet been widely adopted. Identification of human-specific metabolic pathways along with any saturable pathways (as indicated by nonlinear PK) guides further refinement of victim DDI potential at FIH stage.…”

“…Recent advances in clinical devices as Entero-Test (Guiney et al, 2011;Bloomer et al, 2013) have enabled direct assessment of drugs and metabolites excreted into the bile of humans. This method can be applied in early clinical development to provide qualitative information on the risk of interactions for drugs that are metabolized and eliminated in bile.…”

Understanding the Transport Properties of Metabolites: Case Studies and Considerations for Drug Development

“…Application of the Entero-Test has been reported by Bloomer et al (2013), who used this approach to study the metabolism of GSK1325756 (N-(4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl)-N9-(3-fluoro-2-methylphenyl)urea), a drug undergoing development for chronic obstructive pulmonary disease. Preliminary in vitro and preclinical studies suggested that the drug underwent direct conjugation, with this conjugate eliminated in bile, as well as additional drug clearance by oxidative metabolism.…”