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Quantifying gut wall metabolism: methodology matters

Oliver Hatley,Christopher R. Jones,A. Galetin,A. Rostami-Hodjegan

Published 2017 in Biopharmaceutics & drug disposition

ABSTRACT

Oral administration continues to be the dominant route for the dosing of small molecules. Therefore having adequate oral bioavailability remains a key component for the success of drug candidates. Amongst various factors determining the overall bioavailability, the role of the intestinal metabolism is commonly overlooked [1]. Intestinal microsomes are commercially available, analogous to hepatic microsomes that are an essential part of the early drug discovery DMPK (Drug Metabolism and Pharmacokinetics) assessment. This disregard of intestinal metabolism is therefore not due to a lack of available in vitro tools, but a caveat of several confounding factors: the historical low activities in intestinal metabolism assays, and the absence of definitive scaling approaches for reliable quantitative extrapolation of the data generated. These factors are closely linked to the difficulties of producing reproducible intestinal microsomes and complications associated with heterogeneity of the small intestine relative to the liver, which may all explain why in vitro–in vivo extrapolation (IVIVE) of intestinal metabolism has not reached the same level of characterization as that of the liver. In this context, the published intestinal microsome preparation methods reveal a vast array of preparation techniques. These methodologies affect both the quality of the in vitro microsomal matrix, as well as confidence in defining absolute quantification of the intestinal metabolism component using scaling factors and IVIVE.

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