Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Keitaro KadonoToshio Teramura

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 val...Continue Reading

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Citations

Apr 30, 2010·Pharmaceutical Research·Cuyue Tang, Thomayant Prueksaritanont
Sep 28, 2013·Pharmaceutical Research·Andrés Olivares-MoralesAmin Rostami-Hodjegan
Sep 1, 2011·Drug Metabolism and Pharmacokinetics·Haruka NishimutaSetsuko Komuro
Oct 6, 2011·Drug Metabolism and Pharmacokinetics·Takako FurukawaToshio Teramura
Mar 16, 2011·Journal of Biomedicine & Biotechnology·Offie P SoldinDonald R Mattison
Sep 22, 2010·Annual Review of Pharmacology and Toxicology·Malcolm RowlandGeoffrey Tucker
Jan 15, 2013·Journal of Pharmaceutical Sciences·Johan Bylund, Tjerk Bueters
Feb 22, 2011·Bioorganic & Medicinal Chemistry Letters·Phillip M CowleyGrant Wishart
Aug 22, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Takako FurukawaToshio Teramura
Dec 18, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Keitaro KadonoToshio Teramura
Jan 3, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Tjerk BuetersJohan Bylund
May 1, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Takako FurukawaToshio Teramura
Mar 12, 2015·Drug Metabolism and Pharmacokinetics·Yoichi NaritomiKenji Tabata
Feb 6, 2017·Biopharmaceutics & Drug Disposition·Estelle YauSheila Annie Peters
Jun 12, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Fumihiro NakamoriToshio Teramura
Aug 7, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Fredrik H KarlssonSheila Annie Peters
Jun 8, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keigo KosakaToshiyuki Kume
Nov 22, 2018·Frontiers in Physiology·Pablo Torres-VergaraJeffrey Penny

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