Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent

Chen, C. L.; Sangiah, S.; Bourne, David W. A.; Roder, Joseph D.; Chen, H.; Alavi, Fereidon K.; Clarke, Cyril R.; Garrison, G. L.; Berlin, K. Darrell; Couch, Kevin M.; Zisman, Stan A.; Scherlag, Benjamin J.; Lazzara, Ralph; Helm, D. van der

doi:10.1007/bf03226370

Cited by 12 publications

(5 citation statements)

References 18 publications

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“…An appropriate pharmacokinetic model was chosen based on the lowest Akaike’s information criterion (AIC) value, lowest weighted squared residuals, lowest standard errors of the fitting parameters, and dispersion of the residual under equal weight scheme [25–27]. All the data were expressed as the mean ± standard deviation and the levels of statistical significance were assessed using Student t test.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Tissue Distribution Study of Praeruptorin D from Radix Peucedani in Rats by High-Performance Liquid Chromatography (HPLC)

Tang

Yue²,

Du³

et al. 2012

IJMS

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Praeruptorin D (PD), a major pyranocoumarin isolated from Radix Peucedani, exhibited antitumor and anti-inflammatory activities. The aim of this study was to investigate the pharmacokinetics and tissue distribution of PD in rats following intravenous (i.v.) administration. The levels of PD in plasma and tissues were measured by a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. The biosamples were treated by liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE) and osthole was used as the internal standard (IS). The chromatographic separation was accomplished on a reversed-phase C18 column using methanol-water (75:25, v/v) as mobile phase at a flow rate of 0.8 mL/min and ultraviolet detection wave length was set at 323 nm. The results demonstrate that this method has excellent specificity, linearity, precision, accuracy and recovery. The pharmacokinetic study found that PD fitted well into a two-compartment model with a fast distribution phase and a relative slow elimination phase. Tissue distribution showed that the highest concentration was observed in the lung, followed by heart, liver and kidney. Furthermore, PD can also be detected in the brain, which indicated that PD could cross the blood-brain barrier after i.v. administration.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Tissue Distribution Study of Praeruptorin D from Radix Peucedani in Rats by High-Performance Liquid Chromatography (HPLC)

Tang

Yue²,

Du³

et al. 2012

IJMS

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“…All incubation mixtures contained the following ingredients (a modified procedure of Chen et al, 1995Chen et al, , 1999b at the indicated final concentrations (200 l): 1ϫ PBS, microsomes (1 mg/ml), glucose 6-phosphate (10 mM), glucose-6-phosphate dehydrogenase (2 units/ml), and MgCl 2 (5 mM). The mixtures were preincubated at 37°C for 5 min.…”

Section: Methodsmentioning

confidence: 99%

CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by RegioselectiveO-Demethylation

Uckun

Thoen²,

Chen³

et al. 2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Here we report the phase I metabolism of the rationally designed Janus kinase-3 (JAK) inhibitor 4-(4-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131; JANEX-1). JANEX-1 was metabolized by the cytochrome P450 enzymes CYP1A1 and CYP1A2 in a regioselective fashion to form the biologically inactive 7-O-demethylation product 4-(4-hydroxyphenyl)-amino-6-methoxy-7-hydroxyquinazoline (JANEX-1-M). Our molecular modeling studies indicated that the CYP1A family enzymes bind and demethylate JANEX-1 at the C-7 position of the quinazoline ring since the alternative binding conformation with demethylation at the C-6 position would result in a severe steric clash with the binding site residues. The metabolism of JANEX-1 to JANEX-1-M in pooled human liver microsomes followed Michaelis-Menten kinetics with Acute allergic reactions, also known as immediate (type I) hypersensitivity reactions, including anaphylaxis with a potentially fatal outcome, are triggered by three major classes of proinflammatory mediators, namely preformed granule-associated bioactive amines (e.g., histamine, serotonin) and acid hydrolases (e.g., ␤-hexosaminidase), newly synthesized arachidonic acid metabolites (e.g., leukotriene C 4 , prostaglandin D 2 , and platelet activating factor), and a number of proinflammatory vasoactive cytokines [e.g., tumor necrosis factor (TNF 1 )-␣ and interleukin-6] (Galli, 1993). These proinflammatory mediators are released from sensitized mast cells upon activation through the antigen-mediated cross-linking of their high-affinity cell surface IgE receptors/Fc epsilon (⑀) RI (Galli, 1993;Malaviya et al., 1993). IgE receptor/Fc⑀RI is a multimeric receptor with ␣-, ␤-, and homodimeric ␥-chains. Both ␤-and ␥-subunits of the IgE receptor/ Fc⑀RI contain immunoreceptor tyrosine-based activation motifs, which allow interaction with protein tyrosine kinases (PTK) and PTK substrates via their SH2 domains (Scharenberg et al., 1995). The engagement of IgE receptors by antigen triggers a cascade of biochemical signal transduction events, including activation of multiple PTK (Scharenberg et al., 1995). The activation of PTK and subsequent tyrosine phosphorylation of their downstream substrates have been implicated in the pathophysiology of type I hypersensitivity reactions (Scharenberg et al., 1995). The elucidation of the PTKdependent signal transduction events that lead to Fc⑀RI-mediated mast cell degranulation and mediator release may provide the basis for the rational design of potent mast cell inhibitors for prevention and treatment of allergic reactions.In a recent study, we found that the IgE/antigen induced degranulation and mediator release are substantially reduced with Jak3 Ϫ/Ϫ mast cells from JAK3-null mice that were generated by targeted disruption of the Jak3 gene in embryonic stem cells , indicating that JAK3 plays a pivotal role in IgE receptor/Fc⑀RI-mediated mast cell responses both in vitro and in vivo. We subsequently reported that treatment...

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“…An appropriate pharmacokinetic model was chosen based on the lowest Akaike's information criterion (AIC) value, the lowest weighted squared residuals, the lowest standard errors of the fitting parameters, and the dispersion of the residual under an equal weight scheme (Chen et al, 1995(Chen et al, , 2001a(Chen et al, ,b, 2002Gabrielsson and Weiner, 1997). The area under the curve (AUC) was calculated by the trapezoidal rule between the first (0 h) and last (8 h) sampling time plus C n / n , where C n is the concentration of last sampling, and n is the elimination rate constant (Zhang et al, 2006).…”

Section: Pharmacokinetics Analysismentioning

confidence: 99%

Pharmacokinetics of salvianolic acids after intravenous injection, with and without Panax quinquefolium protopanaxadiol saponins, in rats

Yang

Wang

Liu

et al. 2008

Journal of Ethnopharmacology

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Metabolism and metabolite pharmacokinetics of BRB-I-28, a class Ib antiarrhythmic agent

Cited by 12 publications

References 18 publications

Pharmacokinetics and Tissue Distribution Study of Praeruptorin D from Radix Peucedani in Rats by High-Performance Liquid Chromatography (HPLC)

Pharmacokinetics and Tissue Distribution Study of Praeruptorin D from Radix Peucedani in Rats by High-Performance Liquid Chromatography (HPLC)

CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4′-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by RegioselectiveO-Demethylation

Pharmacokinetics of salvianolic acids after intravenous injection, with and without Panax quinquefolium protopanaxadiol saponins, in rats

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