Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Kadono, Keitaro; Akabane, Takafumi; Tabata, Kenji; Gato, Katsuhiko; Terashita, Shigeyuki; Teramura, Toshio

doi:10.1124/dmd.109.029322

Cited by 52Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug Solubulity and Delivery Systems

Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

Kadono, Keitaro, Akabane, Takafumi, Tabata, Kenji, Gato, Katsuhiko, Terashita, Shigeyuki, Teramura, Toshio·2010·Drug Metabolism and Disposition

DOI 10.1124/dmd.109.029322

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Abstract

This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans.

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When IVIVE is not successful in preclinical species, it may be necessary to use empirical scaling factors for human prediction.
“When IVIVE is not successful in preclinical species it may be necessary to use empirical scaling factors for the human prediction (as for Compound 1 in Sect. 4.1) [47-49].”
From Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies (2019) · cites this paper as [47]

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Retracted

Authors: Kadono, K., Akabane, T., Tabata, K., Gato, K., Terashita, S., & Teramura, T.
Affiliations: Astellas Pharma (Japan) (JP)
Venue: Drug Metabolism and Disposition
Publisher: Elsevier BV
Published: 2010-07
Volume: 38
Issue: 7
Pages: 1230-1237
ISSN: 0090-9556 (ISSN-L)
DOI: 10.1124/dmd.109.029322
OpenAlex: W2144062256
Cited by: 52
References: 42
Citations by year: 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 6 · 2012: 9
FWCI: 7.44
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Drug Metabolism and Disposition (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Keywords: intestinal metabolism, CYP3A4, P-glycoprotein, drug absorption prediction, pharmacokinetics, drug discovery
MeSH terms: Biological Availability, Drug Evaluation, Preclinical, Forecasting, Humans, Intestinal Mucosa, Microsomes, Models, Theoretical, Permeability, Pharmacokinetics, ATP Binding Cassette Transporter, Subfamily B, Member 1, Cytochrome P-450 CYP3A, In Vitro Techniques

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Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor

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