A validated enantioselective LC–MS/MS assay for quantification of a major chiral metabolite of an achiral 11-β-hydroxysteroid-dehydrogenase 1 inhibitor in human plasma: Application to a clinical pharmacokinetic study

Furlong, Melissa; Ji, Qin; Iacono, Lisa; Dang, Oanh; Noren, Marzena; Bruce, John; Aubry, Anne‐Françoise; Arnold, Mark E.

doi:10.1016/j.jchromb.2016.03.043

Cited by 5 publications

(7 citation statements)

References 16 publications

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“…In the evaluation of both analytical methods, no carryover was observed between two sample injections. The concentration of BMS‐823778 in human plasma and urine samples was quantified using a validated LC–MS/MS method using [ 13 C 2 , D 6 ]BMS‐823778 as reported previously .…”

Section: Methodsmentioning

confidence: 99%

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

Cheng

Wang

Iacono

et al. 2017

Brit J Clinical Pharma

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AIMSBMS-823778 is an inhibitor of 11β-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials. METHODSThe metabolism of BMS-823778 was characterized in multiple in vitro assays. Pharmacokinetics were evaluated in healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor metabolizers (PM), with a single oral dose of [ 14 C]BMS-823778 (10 mg, 80 μCi). RESULTSThree metabolites (<5%) were identified in human hepatocytes and liver microsomes (HLM) incubations, including two hydroxylated metabolites (M1 and M2) and one glucuronide conjugate (M3). As the most abundant metabolite, M1 was formed mainly through CYP2C19. M1 formation was also correlated with CYP2C19 activities in genotyped HLM. In humans, urinary excretion of dosed radioactivity was significantly higher in EM (68.8%; 95% confidence interval 61.3%, 76.3%) than in PM (47.0%; 43.5%, 50.6%); only small portions (<2%) were present in faeces or bile from both genotypes. In plasma, BMS-823778 exposure in PM was significantly (5.3-fold, P = 0.0097) higher than in EM. Furthermore, total radioactivity exposure was significantly higher (P < 0.01) than BMS-823778 exposure in all groups, indicating the presence of metabolites. M1 was the only metabolite observed in plasma, and much lower in PM. In urine, the amount of M1 and its oxidative metabolite in EM was 7-fold of that in PM, while more glucuronide conjugates of BMS-823778 and M1 were excreted in PM. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• BMS-823778 is a potent inhibitor of 11β-hydroxysteroid dehydrogenase type-1 and developed for the treatment of Type 2 diabetes.• In early clinical trials, the plasma concentration profiles of BMS-823778 were highly variable among individual subjects.• Preliminary analysis indicated that BMS-823778 had a higher exposure in one CYP2C19 poor metabolizer. WHAT THIS STUDY ADDS• In vitro assays demonstrated that CYP2C19 was a major enzyme involved in BMS-823778 metabolism.• The plasma exposure of BMS-823778 was significantly higher in CYP2C19 poor metabolizers than in extensive metabolizers.• In vitro to in vivo extrapolation under predicted the difference of BMS-823778 plasma exposure between CYP2C19 poor metabolizers and extensive metabolizers.

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Section: Methodsmentioning

confidence: 99%

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

Cheng

Wang

Iacono

et al. 2017

Brit J Clinical Pharma

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“…Genotyping for CYP2C19, CYP3A5, and UGT1A4 was performed on the drug metabolism enzymes and transporters microarray using the DMET Plus Premier pack kits as described previously (Cheng et al, 2018). Plasma and urine concentrations of BMS-8237778 were determined with validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods reported previously (Furlong et al, 2016). Details about the methods-including internal standard, method of extraction, high-performance liquid chromatography column and mobile phase, monitored m/z transitions, within-and between-day variability-were described therein.…”

Section: Methodsmentioning

confidence: 99%

“…BMS-823778 is a potent and selective inhibitor of 11b-HSD1 with an in vitro IC 50 value of ;3 nM (Li et al, 2014;Furlong et al, 2016). As part of clinical development, the pharmacokinetics (PK), safety, and tolerability of BMS-823778 were characterized in several clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects

2018

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BMS-823778 is a potent and selective inhibitor of 11-HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 and UGT1A4. The clinical pharmacokinetics (PK) of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after the oral dose, and systemic exposure at steady state increased proportionally to the dose. Large intersubject variability in BMS-823778 exposure was likely because of the polymorphism of metabolic enzymes. The impact of genetic polymorphism of CYP2C19, UGT1A4, and CYP3A5 on BMS-823778 PK was assessed in healthy Chinese and Japanese subjects, as well as in a human absorption, distribution, metabolism, and excretion study in which all subjects were genotyped either before or after treatment. A clear trend of high exposure and low clearance was seen in poor metabolizers (PMs) of CYP2C19 compared with extensive (EM) and intermediate metabolizer (IM) subjects. The impact of UGT1A4 or CYP3A5 polymorphism on BMS-823778 PK was statistically not significant in CYP2C19 EM and IM subjects; however, in a subject with predicted CYP2C19 PM phenotype, the PK of BMS-823778 was affected significantly by UGT1A4 polymorphism. Overall, BMS-823778 was safe and well tolerated in healthy subjects after single or multiple oral doses. The PK of BMS-823778 was characterized by rapid absorption, and the systemic clearance directly correlated with the genetic polymorphism of CYP2C19.

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“…have also been determined, especially in commercial products or biological samples (pharmaceutical formulations, human urine, human or animal blood, human plasma, animal serum, etc.). Another heterogeneous group of analytes, including connectors for building metal-organic frameworks [116,117,124], intermediates for the synthesis of pharmaceuticals [111], natural and synthetic compounds [39,113,121,120], biological compounds [82,112,58,71,78,86,[61][62][63]77,75], natural alkaloids [121], biomolecules [115,54], organometallic compounds [119] and chiral metabolites [103,108,100,97,102,59,63,52] has been enantioseparated with these immobilized polysaccharides CSPs (see Table 2-4). Fig.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Several studies carried out on certain polysaccharide-based CSPs of immobilized type showed significant effects of acidic additive (or acidic with basic mixture additive) mainly on basic compounds [41,103,104,108,101,73,53,95,90,91,58,86,63,115,52] (see Tables 2-4).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

State-of-the-art and recent developments of immobilized polysaccharide-based chiral stationary phases for enantioseparations by high-performance liquid chromatography (2013–2017)

Padró

Keunchkarian

2018

Microchemical Journal

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Please cite this article as: Juan M. Padró, Sonia Keunchkarian , State-of-the-art and recent developments of immobilized polysaccharide-based chiral stationary phases for enantioseparations by high-performance liquid chromatography (2013)(2014)(2015)(2016)(2017). AbstractPolysaccharide-based chiral stationary phases have been recognized as one of the most powerful ones for high performance liquid chromatography (HPLC) separations of chiral compounds in analytical and also in preparative scale.Immobilized polysaccharide-based chiral stationary phases constitute a remarkable achievement due to their stable nature on working with standard or common solvents and also with those prohibited for using with coated phases.This review is mainly focused on the i. applications of these chiral stationary phases in numerous fields of HPLC separations; ii. comparative aspects between immobilized vs. coated polysaccharide-derived phases, and iii. revision of several theoretical studies such as enantiorecognition mechanism, mobile phase composition and column temperature effects.

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A validated enantioselective LC–MS/MS assay for quantification of a major chiral metabolite of an achiral 11-β-hydroxysteroid-dehydrogenase 1 inhibitor in human plasma: Application to a clinical pharmacokinetic study

Cited by 5 publications

References 16 publications

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects

State-of-the-art and recent developments of immobilized polysaccharide-based chiral stationary phases for enantioseparations by high-performance liquid chromatography (2013–2017)

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