2020
DOI: 10.1124/dmd.120.000111
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Evaluation of In Vitro Models for Assessment of Human Intestinal Metabolism in Drug Discovery

Abstract: Although intestinal metabolism plays an important role in drug disposition, early predictions of human outcomes are challenging, in-part due to limitations of available in vitro models. To address this, we have evaluated three in vitro models of human intestine (microsomes, permeabilized enterocytes, and cryopreserved intestinal mucosal epithelium) as tools to assess intestinal metabolism and estimate the fraction escaping gut metabolism (f g) in drug discovery. The models were tested with a chemically diverse… Show more

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Cited by 19 publications
(14 citation statements)
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“…While MRP3 can efflux raloxifene-Gs into blood from hepatocytes, the high recovery of administered raloxifene in feces supports predominant biliary excretion as a consequence of high MRP2 transport and high net uptake into hepatocytes, likely mediated by OATPs. Although raloxifene undergoes sulfate conjugation in human enterocytes, intestinal microsomes and liver microsomes, raloxifene sulfates were not detected in human plasma ( Food and Drug Administration, 1999 ; Hui et al, 2015 ; Davies et al, 2020 ). The systemic absorption of raloxifene sulfates may be limited by apical efflux transporters ( Jeong et al, 2004 ; Zhou et al, 2015 ).…”
Section: Interplay Of Uptake and Efflux Transport In Drug Conjugate D...mentioning
confidence: 99%
“…While MRP3 can efflux raloxifene-Gs into blood from hepatocytes, the high recovery of administered raloxifene in feces supports predominant biliary excretion as a consequence of high MRP2 transport and high net uptake into hepatocytes, likely mediated by OATPs. Although raloxifene undergoes sulfate conjugation in human enterocytes, intestinal microsomes and liver microsomes, raloxifene sulfates were not detected in human plasma ( Food and Drug Administration, 1999 ; Hui et al, 2015 ; Davies et al, 2020 ). The systemic absorption of raloxifene sulfates may be limited by apical efflux transporters ( Jeong et al, 2004 ; Zhou et al, 2015 ).…”
Section: Interplay Of Uptake and Efflux Transport In Drug Conjugate D...mentioning
confidence: 99%
“…The experimental set-up for the enzyme kinetics and substrate binding might be a reason for these differences, as also might the enzyme sources, and their resultant activities (Davies et al, 2020;Trdan Lušin et al, 2011). The conclusion here is thus that the reliability of any comparisons of data from different laboratories between sulfation and glucuronidation, and also between the different bisphenols, is only limited at best.…”
Section: Bpa Sulfationmentioning
confidence: 93%
“…57,58 CHIM is found to be a useful experimental model for the evaluation of first-pass intestinal metabolism of orally administered drugs for the estimation of the fraction escaping gut metabolism, especially for moderately and rapidly metabolized drugs. 59 CHIM has been applied towards the evaluation of DDI potential of commercial formulations of herbal supplements, identifying green tea extract, St. John's wort, valerian root, horehound, and grapefruit juice as having potent CYP3A inhibition/induction potentials, and suggesting potential for herb-drug interaction with orally administered drugs that are Accepted Article CYP3A substrates. 60 CHIM as an experimental tool for the evaluation of intestinal drug toxicity is illustrated by dose-dependent cytotoxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen and naproxen, with naproxen exhibiting a higher enterotoxicity than acetaminophen as in humans in vivo.…”
Section: Novel In Vitro Enteric Models For Ddis and Safety Evaluationmentioning
confidence: 99%
“…Inter‐regional and interindividual evaluation of enteric drug metabolism have been evaluated with CHIM, with the proximal jejunum in general exhibiting higher drug metabolizing enzyme activities than those in duodenum and ileum, and with significant interindividual variations, especially for the inducible P450 isoforms 57,58 . CHIM is found to be a useful experimental model for the evaluation of first‐pass intestinal metabolism of orally administered drugs for the estimation of the fraction escaping gut metabolism, especially for moderately and rapidly metabolized drugs 59 . CHIM has been applied toward the evaluation of DDI potential of commercial formulations of herbal supplements, identifying green tea extract, St. John’s wort, valerian root, horehound, and grapefruit juice as having potent CYP3A inhibition/induction potentials, and suggesting potential for herb‐drug interaction with orally administered drugs that are CYP3A substrates 60 .…”
Section: D In Vitro Intestine Modelsmentioning
confidence: 99%