Methods To Evaluate Biliary Excretion of Drugs in Humans:  An Updated Review

Abstract

Determining the biliary clearance of drugs in humans is very challenging because bile in not readily accessible due to the anatomy of the hepatobiliary tract. The collection of bile usually is limited to post-surgical patients with underlying hepatobiliary disease. In healthy subjects, feces typically are used as a surrogate to quantify the amount of drug excreted via non-urinary pathways. Nevertheless, it is very important to characterize hepatobiliary elimination because this is a potential site of drug interactions that might result in significant alterations in systemic or hepatic exposure. In addition to the determination of in vivo biliary clearance values of drugs, the availability of in vitro models that can predict the extent of biliary excretion of drugs in humans may be a powerful tool in the preclinical stages of drug development. In this review, recent advances in the most commonly used in vivo methods to estimate biliary excretion of drugs in humans are outlined. Additionally, in vitro models that can be employed to investigate the molecular processes involved in biliary excretion are discussed to present an updated picture of the new tools and techniques that are available to study the complex processes involved in hepatic drug transport.

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

“…While human liver microsomes generally provide reliable predictions of human metabolic clearance for extensively metabolized drugs (8)(9)(10)(11)(12)(13) and renal clearance is not difficult to determine, predictions of human biliary clearance are difficult and scarce, despite ongoing efforts (14). Clinical methods include bile duct cannulation during surgery, collection of duodenal fluid in healthy volunteers, or fecal collections.…”

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

“…Likewise, compounds 3, 4, 5, 6, 11and 13 will be eliminated majorly via the faecal route as have molecular weight greater than 350 Da. All the other compounds, including lead compound 1 will eliminate partially via renal and the faecal route due to molecular weight range from 250-350 Da (Ghibellini et al 2006). Similarly, the highest log D value possessed by the lead compound 1 > 8 > 6 >13 also conferred them to be released metabolically via bile canaliculi and faecal route (Smith et al 1996).…”

Toxicokinetics and Organ-Specific Toxicity

“…For example, development of valid and reliable techniques to quantify biliary excretion of drugs in healthy human volunteers is difficult. Measurements of drug concentrations in bile can only be obtained from patients diagnosed with diseases of the gallbladder and biliary tract who require medical procedures that allow this measurement (Ghibellini et al, 2006). However, there is a promising, recent technique to estimate bile in healthy human volunteers with an oroenteric catheter to aspirate duodenal secretions, and gamma scintigraphy to determine gallbladder contraction.…”