Determination ofin vitro permeability of drug candidates through a Caco-2 cell monolayer by liquid chromatography/tandem mass spectrometry

Wang, Zhen; Hop, Cornelis E. C. A.; Leung, Kwan; Pang, Jianmei

doi:10.1002/(sici)1096-9888(200001)35:1<71::aid-jms915>3.0.co;2-5

Cited by 93 publications

(51 citation statements)

References 20 publications

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“…Caco-2 cell monolayers with TEER values greater than 500 Ω cm 2 were considered for experimentation. Digoxin (5 µM) was used as a positive control for P-gp substrate [10]. The concentration of ulixertinib used in the assay was 10 µM.…”

Section: Caco-2 Permeabilitymentioning

confidence: 99%

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Balakrishna

Hiremath²,

Raj³

et al. 2017

ADMET DMPK

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Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 µM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %.

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Section: Caco-2 Permeabilitymentioning

confidence: 99%

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Balakrishna

Hiremath²,

Raj³

et al. 2017

ADMET DMPK

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“…For the analysis of samples from in vitro permeability tests [8][9][10][11][12], high performance liquid chromatography (HPLC) coupled with mass spectrometric detection has been widely used. LC/MS/MS offers the advantages of increased sensitivity and specificity [13].…”

Section: Introductionmentioning

confidence: 99%

Novel generic UPLC/MS/MS method for high throughput analysis applied to permeability assessment in early Drug Discovery

Mensch

Noppe

Adriaensen

et al. 2007

Journal of Chromatography B

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“…The trapped analytes are back-eluted from the on-line trap column and further chromatographically resolved on a second analytical C18 column. Combining the TFC technique with the specificity of a mass spectrometer operating in the selected reaction monitoring mass spectrometry (SRM) mode permits Caco-2 cell analysis in a cassette N-in-1 mode [21][22][23][24]. Several different researchers have published papers for utilizing cassette mode approach.…”

Section: Introductionmentioning

confidence: 99%