Andrew Augustine, MS, Senior Study Director, DMPK
One of the primary functions of the liver is to manufacture bile, which is necessary for the digestion of fat and elimination of drugs and their metabolites. Metabolism of drugs by the liver determines clearance and bioavailability. Rats are typically the first species used to characterize drug clearance, bioavailability, and biliary drug disposition.
When conducting ADME studies, MPI Research is often asked, by our Sponsors, whether or not they should include a bile-duct cannulated (BDC) animal group as part of the study design. For small molecules, the answer is a resounding YES. This is both to determine involvement with enterohepatic recirculation, and also to provide bile for subsequent radiochromatographic profiling and metabolite identification. The majority of drugs currently being developed are large (>500 Da molecular weight) cholephilic compounds excreted in the bile via sinusoidal uptake transporters (i.e., OATP and OCT) and biliary canalicular efflux transporters (i.e., MRP2, BCRP, and MDR/Pgp).
Regarding timelines for bile sample collection: The process of biliary excretion is quite quick, and we typically recommend collecting for 72 hours post-dose. In our experience, the trend we’ve seen with single-dose administration, the bile will usually come out maximally within the first 24 hours – after which it clears at a slower rate. In many cases, it is best to divide the first 24-hour collection period into 0–8 and 8–24, or 0–6, 6–12, and 12–24 hours. Most often, test articles have been observed to come out very quickly in the bile if enterohepatic recirculation is indeed occurring.
When working with rodents, it is more cost-effective for a CRO to purchase bile-duct cannulated rats from a supplier. For large animals, the CRO must perform these BDC surgeries in-house, and the cost is passed on to the Sponsor, which comes at a high price. For many years, the “gold standard” for large animal bile-duct cannulation was the well-known “Kissinger model,” where BDC animals could be kept functional and patient for many months, sometimes years. But a noticeable decrease in requests for BDC large animals makes it cost-prohibitive for a CRO to maintain colonies of animals, for this purpose. Many CROs have either stopped offering large animal BDC capabilities altogether, or have switched to one-time-use acute models for their large animal BDC studies.
It is important to consider BDC studies when designing larger ADME and safety studies for small molecules. MPI Research has the expertise to guide timing of study collections, and species selection, while remaining cost-conscious – in order to provide quality data.