Development and validation of a high performance liquid chromatography method for determination of 6‐benzyl‐1‐benzyloxymethyl‐5‐iodouracil (W‐1), a novel non‐nucleoside reverse transcriptase inhibitor and its application to a pharmacokinetic study in rats

Lu, Yingyuan; Wang, Xin; Wang, Xiaowei; Liu, Junyi; Li, Pu; Ren, Hongqiang; Lou, Ya-Qing; Lu, Chuang; Zhang, Guoliang

doi:10.1002/bmc.3457

Cited by 4 publications

(2 citation statements)

References 22 publications

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“…Plasma concentration of W-1 in biological sample was determined using a validated HPLC method as described earlier (Lu et al 2015). Briefly, the analysis was performed using a HPLC consistent of model 510 pump with a model 2487 ultraviolet detector, a model Rheodyne 7725 injector, and a column oven.…”

Section: Hplc Analysis and Methods Validationmentioning

confidence: 99%

“…Therefore W-1 could have the potential to be next generation of drug candidate for treatment of acquired immunodeficiency syndrome (AIDS). In our earlier research, a sensitive and selective HPLC method for determination of W-1 in plasma has been developed and validated (Lu et al 2015). However, the expanding pharmacokinetic researches consisting of absorption, distribution and excretion profile have not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Wang

et al. 2016

Arch. Pharm. Res.

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The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

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Section: Hplc Analysis and Methods Validationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Wang

et al. 2016

Arch. Pharm. Res.

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Pharmacokinetics study of 16 representative components from Baoyuan Decoction in rat plasma by LC–MS/MS with a large-volume direct injection method

Chen

Song

et al. 2019

Phytomedicine

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Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) using human recombinant enzymes and rat liver microsomesin vitro

Cheng

Wang

et al. 2017

Xenobiotica

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1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) in rat and human in vitro. 2. The parent drug of W-1 was incubated with rat liver microsomes (RLMs) or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5, respectively) in the presence or absence of nicotinamide adeninedinucleotide phosphate (NADPH)-regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). 3. The parent drug of W-1 was metabolized in a NADPH-dependent manner in RLMs. The kinetic parameters of prototype W-1 including K, V, and CL were 2.3 μM, 3.3 nmol/min/mg protein, and 1.4 mL/min/mg protein, respectively. Two metabolites M1 and M2 were observed in shorter retention times (2.988 and 3.188 min) with a higher molecular ion at m/z 463.0160 (both M1 and M2) than that of the W-1 parent drug (6.158 min with m/z 447.0218). The CYP selective inhibition and recombinant enzymes also showed that two hydroxyl metabolites M1 and M2 are mainly mediated by CYP2C19 and CYP3A4. 4. The identification of CYPs involved in W-1 biotransformation is important to understand and minimize, if possible, the potential of drug-drug interactions.

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Development and validation of a high performance liquid chromatography method for determination of 6‐benzyl‐1‐benzyloxymethyl‐5‐iodouracil (W‐1), a novel non‐nucleoside reverse transcriptase inhibitor and its application to a pharmacokinetic study in rats

Cited by 4 publications

References 22 publications

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Pharmacokinetics study of 16 representative components from Baoyuan Decoction in rat plasma by LC–MS/MS with a large-volume direct injection method

Identification of cytochrome P450s involved in the metabolism of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) using human recombinant enzymes and rat liver microsomesin vitro

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