Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude

Zhou, Xuejiao; Nian, Yongqiong; Qiao, Yijie; Yang, Meihua; Xin, Yuanyao; Li, Xiangyang

doi:10.2174/1389200219666180529112913

Cited by 26 publications

(22 citation statements)

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“…Of these, the Qinghai-Tibetan plateau is the largest and highest in the world, with almost 9 million inhabitants living in long-term high-altitude hypoxia. In recent years, more people have moved to the plateau regions due to social and economic development (Zhou et al, 2018). Hypoxia-induced fluctuations in organism function, metabolism, and structure underly the pathological basis of disease at high altitude (Zhou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, more people have moved to the plateau regions due to social and economic development (Zhou et al, 2018). Hypoxia-induced fluctuations in organism function, metabolism, and structure underly the pathological basis of disease at high altitude (Zhou et al, 2018). High-altitude hypoxia has negative effects on the cardiovascular system, nervous system, and metabolism, which contribute to potential changes in drug metabolism (Mairbaurl, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…For example, the clearance (CL) and volume of distribution (Vd) of diltiazem were significantly decreased under hypoxia. Hypoxia also altered the disposition of propranolol, significantly decreasing the area under the curve (AUC), mean residence time (MRT), half-life (T 1/2 ), and peak concentration (C max ) (Zhou et al, 2018). The pharmacokinetic characteristics of drugs can be affected by changes in drug metabolism enzymes induced by hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR

et al. 2020

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Little is known about what roles the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play in drug metabolism in high-altitude hypoxia. Likewise, the potential interaction of nuclear receptors and drug metabolism enzymes during drug metabolism of high-altitude hypoxia is not fully understood. In this work, we investigated the effects of high-altitude hypoxia on transcriptional regulation of cytochrome P450 (CYP450) and UDP-glucuronosyltransferase 1A1 (UGT1A1) genes mediated by PXR and CAR proteins. The protein and mRNA expressions of CYP450, UGT1A1, PXR, and CAR were determined by enzyme-linked immunosorbent assay and qPCR in rats and HepG2 cell lines under hypoxia. Hypoxia potently inhibited the CYP450 isoforms, UGT1A1, PXR, and CAR protein and mRNA expression. To clarify whether PXR and CAR regulate various genes involved in drug metabolism of high-altitude hypoxia, we investigated the expression of CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 using a dualluciferase reporter assay after treatment with Ketoconazole (KCZ) and Retinoic acid (RA), or silenced PXR and CAR gene expression. In HepG2 cells, hypoxia, KCZ, and RA inhibited CYP450 isoforms and UGT1A1 expression. Activation of PXR and CAR in cells treated with 6-(4-chlorophenyl)-imidazo (2,1-b) thiazole-5-carbaldehyde (CITCO) and rifampicin (Rif) resulted in the enhancement of CYP450 isoforms, UGT1A1, PXR, and CAR. In contrast, this effect was not observed under hypoxia. Taken together, our results suggest that hypoxia inhibits CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 expression via the PXR and CAR regulatory pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR

et al. 2020

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“…However, one of the most disturbing findings was the deleterious effect of IH on nGSH growth promotion. While this phenomenon has not been appreciably investigated, particularly in ELGANs who experience frequent IH and apneic events during the first few weeks of life, there are a few studies that have shown that IH impairs drug metabolism [ 64 , 65 , 66 ], suggesting reduced efficacy. This may have a significant impact on pharmacokinetics in ELGANs who are exposed to numerous drugs due to multiple morbidities.…”

Section: Discussionmentioning

confidence: 99%

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model

et al. 2020

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Given the complexity of oxygen-induced retinopathy (OIR), we tested the hypothesis that combination therapies and modes of administration would synergistically optimize efficacy for prevention of OIR. Newborn rats were exposed to neonatal intermittent hypoxia (IH) from the first day of life (P0) until P14 during which they received: (1) oral glutathione nanoparticles (nGSH) with topical ocular phosphate buffered saline (PBS); (2) nGSH with topical ocular Acuvail (ACV); (3) oral coenzyme Q10 (CoQ10) + ACV; (4) oral omega 3 polyunsaturated fatty acids (n-3 PUFAs) + ACV; (5) CoQ10 + n-3 PUFAs + PBS; or (6) CoQ10 + n-3 PUFAs + ACV. Treated groups raised in room air (RA) served as controls. At P14, pups were placed in RA with no treatment until P21. Retinal vascular pathology, ocular angiogenesis biomarkers, histopathology, and morphometry were determined. All combination treatments in IH resulted in the most beneficial retinal outcomes consistent with suppression of angiogenesis growth factors during reoxygenation/reperfusion and no significant adverse effects on somatic growth. nGSH + PBS also reversed IH-induced retinopathy, but had negative effects on growth. Simultaneously targeting oxidants, inflammation, and poor growth mitigates the damaging effects of neonatal IH on the developing retina. Therapeutic synergy with combination delivery methods enhance individual attributes and simultaneously target multiple pathways involved in complex diseases such as OIR.

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“…The metabonomics of drug interventions was a concept originally put forward by Clayton in 2006, 47 and metabonomics analysis of hypoxia drugs at high altitude can be used to determine the changes in endogenous metabolites in hypoxia models after drug interventions. 48 Revealing the metabolic pathways associated with drug interventions and the pharmacological mechanisms of high-altitude hypoxia drugs will improve effective drug treatments and provide new ideas for individualized treatment.…”

Section: Metabonomics Of Drug Interventions In Plateau Hypoxiamentioning

confidence: 99%

Metabonomics window into plateau hypoxia

et al. 2019

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Oxygen deficiency in the plateau environment weakens aerobic metabolism and reduces the energy supply, leading to high-altitude diseases including decreased circulatory function, decreased nutrient and energy supply to tissues and organs, and decreased waste discharge. The involvement of many metabolic pathways is reflected in dramatic changes in levels of endogenous small molecule metabolites. Metabolomics represents a promising technique for mechanistic studies and drug screening, and metabonomics, or quantitative metabolomics, has been increasingly applied to the study of hypoxic diseases and their pathogenesis, as well as to pharmacodynamics at high altitudes. In this article, we review the recent literature on the pathogenesis of altitude hypoxia and the clinical and preclinical metabonomics of drug interventions. Endogenous metabolites and metabolic pathways change significantly under high-altitude hypoxia. Some drug interventions have also been shown to regulate pathway metabolism, and the problems of applying metabonomics to hypoxic diseases at high altitude and the prospects for its future application are summarized.

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Hypoxia Plays a Key Role in the Pharmacokinetic Changes of Drugs at High Altitude

Abstract: The findings of this review have indicated that hypoxia may play a key role in the PK changes of drugs at high altitude. It is suggested that patient living at or traveling to high altitude should be closely monitored, and the dosages of some drugs metabolized should be reduced.

Cited by 26 publications

References 0 publications

Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR

Regulation of High-Altitude Hypoxia on the Transcription of CYP450 and UGT1A1 Mediated by PXR and CAR

Combination Antioxidant/NSAID Therapies and Oral/Topical Ocular Delivery Modes for Prevention of Oxygen-Induced Retinopathy in a Rat Model

Metabonomics window into plateau hypoxia

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