Validation and application of a liquid chromatography–tandem mass spectrometric method for quantification of the drug transport probe fexofenadine in human plasma using 96-well filter plates

Stanton, Melonie L.; Joy, Melanie S.; Frye, Reginald F.

doi:10.1016/j.jchromb.2009.12.022

Cited by 14 publications

(10 citation statements)

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“…Plasma fexofenadine concentrations were determined by validated methods using liquid chromatography tandem mass spectrometry as previously described . The assay was linear over the concentration range of 1.0–500 ng/ml; the precision and accuracy (intra‐ and interrun) were within 4.3% and 8.0%, respectively.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

et al. 2013

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Study Objective-This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and non-glomerular etiologies. Design-A prospective study design Participants-Eighteen adults with CKD Setting-General Clinical Research Center at the University of North Carolina and University of PittsburghMeasurement and Main Results-Blood and urine were collected and assayed for fexofenadine (transporter function) as well as flurbiprofen and 4-hydroxyflurbiprofen (CYP2C9 function). CYP3A4 activity was assessed by the erythromycin breath test. In patients with glomerulonephritis, the apparent oral clearance of fexofenadine (representing transporter activity) was 58.8±34.4L/h, documenting a 40% reduction compared with previous data in healthy controls. The CYP2C9 pathway (4-hydroxyflurbiprofen formation clearance), was similar in all the patients with CKD and was concordant with previous reports of patients with end-stage renal disease (ESRD) and healthy controls. For flurbiprofen, patients with glomerulonephritis had higher oral clearance than those with nonglomeruler CKD, suggesting higher unbound fraction and enhanced metabolism through other (non-CYP2C9) routes. No statistically significant differences in CYP3A4 activity were observed in either group of patients, or when compared with results from previous studies of patients with ESRD or healthy controls. Conclusions-The current study suggests no statistically significant differences in the in vivo activity of CYP2C9 and CYP3A4 in patients with either glomerulonephritis or non-glomerular CKD. However, there are clinical differences in transporter function as defined by at least a 25% reduction in activity in glomerulonephritis as opposed to healthy controls. A similarity in the in vivo function between patients with glomerulonephritis and ESRD, and between patients with glomerulonephritis and non-glomerular CKD was present despite significant differences in kidney function. Further in vivo and in vitro studies are necessary to fully understand the physiologic and disease-specific nuances that contribute to alterations in drug disposition in patients with kidney diseases.

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Section: Methodsmentioning

confidence: 99%

In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

et al. 2013

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“…PF-3084014 may not readily raise A␤1-X, but there are signs that it does modulate ␥-secretase in ways that may not be expected for a compound that is simply inhibiting global ␥-secretase enzymatic activity. Selected nonsteroidal antiinflammatory drugs have been shown to preferentially reduce A␤1-42 relative to A␤1-40 (Takahashi et al, 2003), and brain-penetrant ␥-secretase modulators of multiple chemical series have been described with this profile (Hall et al, 2010;Stanton et al, 2010). A ␥-secretase modulator usually refers to a compound that selectively reduces A␤1-42 and may spare Notch to a greater extent than a ␥-secretase inhibitor, but often results in elevation of smaller A␤ fragments such as A␤1-38 (Hall et al, 2010).…”

Section: Pharmacodynamics and Pharmacokinetics Of Pf-3084014 275mentioning

confidence: 99%

Pharmacodynamics and Pharmacokinetics of the γ-Secretase Inhibitor PF-3084014

Lanz

Wood²,

Richter³

et al. 2010

J Pharmacol Exp Ther

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PF-3084014 [(S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide] is a novel ␥-secretase inhibitor that reduces amyloid-␤ (A␤) production with an in vitro IC 50 of 1.2 nM (whole-cell assay) to 6.2 nM (cell-free assay). This compound inhibits Notch-related T-and B-cell maturation in an in vitro thymocyte assay with an EC 50 of 2.1 M. A single acute dose showed dose-dependent reduction in brain, cerebrospinal fluid (CSF), and plasma A␤ in Tg2576 mice as measured by enzyme-linked immunosorbent assay and immunoprecipitation (IP)/mass spectrometry (MS). Guinea pigs were dosed with PF-3084014 for 5 days via osmotic minipump at 0.03 to 3 mg/kg/day and exhibited dose-dependent reduction in brain, CSF, and plasma A␤. To further characterize A␤ dynamics in brain, CSF, and plasma in relation to drug exposure and Notchrelated toxicities, guinea pigs were dosed with 0.03 to 10 mg/kg PF-3084014, and tissues were collected at regular intervals from 0.75 to 30 h after dose. Brain, CSF, and plasma all exhibited dose-dependent reductions in A␤, and the magnitude and duration of A␤ lowering exceeded those of the reductions in B-cell endpoints. Other ␥-secretase inhibitors have shown high potency at elevating A␤ in the conditioned media of whole cells and the plasma of multiple animal models and humans. Such potentiation was not observed with PF-3084014. IP/MS analysis, however, revealed dose-dependent increases in A␤11-40 and A␤1-43 at doses that potently inhibited A␤1-40 and A␤1-42. PF-3084014, like previously described ␥-secretase inhibitors, preferentially reduced A␤1-40 relative to A␤1-42. Potency at A␤ relative to Notch-related endpoints in vitro and in vivo suggests that a therapeutic index can be achieved with this compound.Amyloid-␤ (A␤) peptide is the primary component of senile plaques (Glenner and Wong, 1984) and is the protein product of a gene [amyloid precursor protein (APP)] whose mutation can result in early-onset Alzheimer's disease. The intersection of this genetic and pathologic evidence has led to a strong focus on A␤ as a major culprit in the etiology of Alzheimer's disease. A number of compounds have advanced to the clinic with the goal of either reducing production of this peptide (e.g., ␤-or ␥-secretase inhibitors) or increasing its clearance from the brain (e.g., A␤ vaccines or monoclonal antibodies). Of these approaches, ␥-secretase has yielded the greatest diversity of chemical tools that enable the study of A␤ pharmacodynamics in animal models and humans. Bioavailable small-molecule inhibitors of ␥-secretase from various chemical series have been shown to rapidly reduce A␤ levels in brain, cerebrospinal fluid (CSF), and plasma from wild-type mice (Yohrling et al., 2007), rats (Best et al., 2005;El Mouedden et al., 2006;Lanz and Schachter, 2006), guinea pigs (Anderson et al., 2005;, and multiple muArticle, publication date, and citation information can be found at

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“…The concentration of total fexofenadine in the biological samples could be measured on the reverse‐phase columns using organic solvent and buffer mobile phases, such as acetonitrile/ammonium acetate and acetonitrile/methanol/trithylamine phosphate . XDB C8 column has been used to determine the racemic fexofenadine in the previous studies .…”

Section: Resultsmentioning

confidence: 99%

Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers

Howard

Myers

2017

Journal of Pharmacy and Pharmacology

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Validation and application of a liquid chromatography–tandem mass spectrometric method for quantification of the drug transport probe fexofenadine in human plasma using 96-well filter plates

Cited by 14 publications

References 31 publications

In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

Pharmacodynamics and Pharmacokinetics of the γ-Secretase Inhibitor PF-3084014

Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers

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