Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing

International Journal of Clinical Pharmacology and Therapeutics
Ichiro IeiriYuichi Sugiyama

Abstract

To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. The AUC and t1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC0-12 ratio of lansoprazole in EMs and PMs was...Continue Reading

Citations

Oct 3, 2015·Leukemia & Lymphoma·Pernille SvendsenHans E Johnsen
Apr 5, 2013·Expert Opinion on Drug Metabolism & Toxicology·Graham LappinTal Burt
May 1, 2015·Clinical Pharmacokinetics·Nicolas HohmannGerd Mikus
Feb 27, 2016·Clinical and Translational Science·Tal BurtMalcolm Rowland
Apr 18, 2017·Journal of Pharmaceutical Sciences·Jingjing YuIsabelle Ragueneau-Majlessi
Dec 22, 2012·Bioanalysis·Robert-Jan An LamersJm Gómez-Guzmán
Sep 10, 2020·Nature Reviews. Drug Discovery·Tal BurtYuichi Sugiyama

Related Concepts

CYP2C19 protein, human
CYP2C9 protein, human
Xenobiotic Monooxygenases
Dextromethorphan, (+-)-Isomer
Neogluconin
Gen-Warfarin
Cytochrome P-450 CYP2D6
Area Under Curve
Organic Anion Transport Polypeptides
Timoprazole Derivatives

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