Application of ultrasound-guided cholecystocentesis to the evaluation of the metabolite profiling in bile of dogs and cynomolgus monkeys.

Elizabeth A Dierks,Maxine Fox,Kimberly Foster,Jamus Macguire,Chiuwa E Luk,James Smalley,Evan Janovitz,Hong Cai,R Marc Fancher,Qin Sun

doi:10.1002/prp2.488

Abstract

In this study, we describe a novel approach for collecting bile from dogs and cynomolgus monkeys for metabolite profiling, ultrasound‐guided cholecystocentesis (UCC). Sampling bile by UCC twice within 24 hours was well tolerated by dogs and monkeys. In studies with atorvastatin (ATV) the metabolite profiles were similar in bile obtained through UCC and from bile duct‐cannulated (BDC) dogs. Similar results were observed in UCC and BDC monkeys as well. In both monkey and dog, the primary metabolic pathway observed for ATV was oxidative metabolism. The 2‐hydroxy‐ and 4‐hydroxyatorvastatin metabolites were the major oxidation products, which is consistent with previously published metabolite profiles. S‐cysteine and glucuronide conjugates were also observed. UCC offers a viable alternative to bile duct cannulation for collection of bile for metabolite profiling of compounds that undergo biliary excretion, given the similar metabolite profiles in bile obtained via each method. Use of UCC for metabolite profiling may reduce the need for studies using BDC animals, a resource‐intensive model.

Highlights

Characterization of the metabolism and disposition of a drug candidate in preclinical species is a routine part of drug discovery and development
In this paper we report on the use of an alternative method for sampling bile from the gallbladders of dogs and monkeys, ul‐ trasound‐guided cholecystocentesis (UCC), to assess the biliary metabolite profile of atorvastatin (ATV)
The mean AUC0‐24h for the metabolites 2‐OH ATV and 2‐OH atorvastatin lactone (ATV‐L) were higher in the plasma samples from the bile duct‐cannulated (BDC) monkeys (Table 3)

Summary

| INTRODUCTION

Characterization of the metabolism and disposition of a drug candidate in preclinical species is a routine part of drug discovery and development This information can assist in the prediction of the major routes of elim‐ ination in man as well as in the interpretation of the clinical ADME data. In this paper we report on the use of an alternative method for sampling bile from the gallbladders of dogs and monkeys, ul‐ trasound‐guided cholecystocentesis (UCC), to assess the biliary metabolite profile of atorvastatin (ATV). This method involves sam‐ pling bile from the gallbladder using a fine needle to aspirate a fixed amount of bile. In the current paper we compare the biliary profile of ATV in dogs and monkeys sampled using UCC to the profiles obtained from bile duct‐cannu‐ lated (BDC) animals

| MATERIALS AND METHODS

Findings

| DISCUSSION