Effect of hypoxia on the pharmacokinetics and metabolism of zaleplon as a probe of CYP3A1/2 activity

Gong, Wenwen; Xu, Ping; Guo, Shaojie; Li, Xiaorong; Jin, Zeng-liang; Zhao, Yuming; Fan, Ming; Xue, Ming

doi:10.1039/c7ra03025h

Cited by 4 publications

(2 citation statements)

References 27 publications

(34 reference statements)

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“…genes and the metabolism of drugs in liver (27,31,48). In our study, the KEGG pathway "drug metabolism-cytochrome P450" was enriched for genes showing differential translation efficiency in both 30-and 240-min hypoxia samples (Fig.…”

Section: G723mentioning

confidence: 62%

Translational and transcriptional responses in human primary hepatocytes under hypoxia

Hettiarachchi

Katneni

Hunt

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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The liver is the primary source of a large number of plasma proteins and plays a critical role in multiple biological processes. Inadequate oxygen supply characterizing various clinical settings such as liver transplantation exposes the liver to hypoxic conditions. Studies assessing hypoxia-induced global translational changes in liver are lacking. Here, we employed a recently developed ribosome-profiling technique to assess global translational responses of human primary hepatocytes exposed to acute hypoxic stress (1% O2) for the short term. In parallel, transcriptome profiling was performed to assess mRNA expression changes. We found that translational responses appeared earlier and were predominant over transcriptional responses. A significant decrease in translational efficiency of several ribosome genes indicated translational inhibition of new ribosome protein synthesis in hypoxia. Pathway enrichment analysis highlighted altered translational regulation of MAPK signaling, drug metabolism, oxidative phosphorylation, and nonalcoholic fatty liver disease pathways. Gene Ontology enrichment analysis revealed terms related to translation, metabolism, angiogenesis, apoptosis, and response to stress. Transcriptional induction of genes encoding heat shock proteins was observed within 30 min of hypoxia. Induction of genes encoding stress response mediators, metabolism regulators, and proangiogenic proteins was observed at 240 min. Despite the liver being the primary source of coagulation proteins and the implicated role of hypoxia in thrombosis, limited differences were observed in genes encoding coagulation-associated proteins. Overall, our study demonstrates the predominance of translational regulation over transcription and highlights differentially regulated pathways or biological processes in short-term hypoxic stress responses of human primary hepatocytes.NEW & NOTEWORTHY The novelty of this study lies in applying parallel ribosome- and transcriptome-profiling analyses to human primary hepatocytes in hypoxia. To our knowledge, this is the first study to assess global translational responses using ribosome profiling in hypoxic hepatocytes. Our results demonstrate the predominance of translational responses over transcriptional responses in early hepatic hypoxic stress responses. Furthermore, our study reveals multiple pathways and specific genes showing altered regulation in hypoxic hepatocytes.

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Section: G723mentioning

confidence: 62%

Translational and transcriptional responses in human primary hepatocytes under hypoxia

Hettiarachchi

Katneni

Hunt

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…All the validation data, such as the precision, accuracy, matrix effect and stability was within the required limit. [24][25][26][27] This method has been successfully used to study the plasma pharmacokinetics and brain distribution kinetics of test drug lapachol in rats, which combined with the microdialysis technique that is a effective method for simultaneously collecting the bio- samples to monitor the local tissue drug concentrations continuously in the awake and unrestrained animals, with the advantages of real-time, live and dynamics. Our results indicated that the in vivo disposition prole of lapachol tted to rst order elimination and two-compartment open model in rat plasma.…”

mentioning

confidence: 99%

Plasma pharmacokinetics and brain distribution kinetics of lapachol in rats using LC-MS and microdialysis techniques

Bai

Han

et al. 2017

RSC Adv.

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The objective of this paper was to investigate the plasma pharmacokinetics and brain distribution kinetics of lapachol in rats. A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of the bioactive naphthoquinone lapachol in rat plasma and brain dialysates after oral administration. The analytes were determined using the negative electrospray ionization mode in multiple reaction monitoring (MRM). The chromatographic separation was on a ZORBAX SB-C18 column coupled with a C18 guard column using a mobile phase composed of acetonitrile-water containing 0.1% formic acid at a flow rate of 0.5 mL min À1 . The methods were sensitive with good linearity and no endogenous material interferences. The inter-and intra-day precision and accuracy of lapachol in plasma and the brain were lower than 12%. The methods were successfully applied to the quantification and pharmacokinetic study of lapachol in rats. The results indicated that the disposition profile of lapachol fitted to first order elimination and the twocompartment open model. Lapachol could pass through the blood brain barrier and went through enterohepatic circulation in rats with extending in vivo exposure time after oral administration. In summary, these findings provide an important pharmacological foundation for developing a novel drug and the clinical use of lapachol.

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A UPLC-MS/MS method reveals the pharmacokinetics and metabolism characteristics of kaempferol in rats under hypoxia

et al. 2022

Drug Metabolism and Pharmacokinetics

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Effect of hypoxia on the pharmacokinetics and metabolism of zaleplon as a probe of CYP3A1/2 activity

Abstract: The objective of this study was to compare the pharmacokinetics and metabolism of zaleplon (ZAL) in rats under hypoxic and normoxic condition and the effect of hypoxia on the protein expression and activities of the main metabolic enzyme CYP3A1/2.

Cited by 4 publications

References 27 publications

Translational and transcriptional responses in human primary hepatocytes under hypoxia

Translational and transcriptional responses in human primary hepatocytes under hypoxia

Plasma pharmacokinetics and brain distribution kinetics of lapachol in rats using LC-MS and microdialysis techniques

A UPLC-MS/MS method reveals the pharmacokinetics and metabolism characteristics of kaempferol in rats under hypoxia

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