Relationship between blood-brain barrier changes and drug metabolism under high-altitude hypoxia: obstacle or opportunity for drug transport?

The blood-brain barrier is essential for maintaining the stability of the central nervous system and is also crucial for regulating drug metabolism, changes of blood-brain barrier's structure and function can influence how drugs are delivered to the brain. In high-altitude hypoxia, the central nervous system's function is drastically altered, which can cause disease and modify the metabolism of drugs in vivo. Changes in the structure and function of the blood-brain barrier and the transport of the drug across the blood-brain barrier under high-altitude hypoxia, are regulated by changes in brain microvascular endothelial cells, astrocytes, and pericytes, either regulated by drug metabolism factors such as drug transporters and drug-metabolizing enzymes. This article aims to review the effects of high-altitude hypoxia on the structure and function of the blood-brain barrier as well as the effects of changes in the blood-brain barrier on drug metabolism. We also hypothesized and explore the regulation and potential mechanisms of the blood-brain barrier and associated pathways, such as transcription factors, inflammatory factors, and nuclear receptors, in regulating drug transport under high-altitude hypoxia.

A Decade's Review of miRNA: A Center of Transcriptional Regulation of Drugmetabolizing Enzymes and Transporters under Hypoxia.

BACKGROUND: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. METHODS: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized. RESULTS: Hypoxia can up or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drugmetabolizing enzymes and transporters. CONCLUSION: The findings of this review indicated that miRNA plays a key role in the expression changes of drugmetabolizing enzymes and transporters under hypoxia.

Effect of X-ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats.

Concurrent chemoradiation with irinotecan hydrochloride (CPT-11) is accepted for cancer treatment. However, the effects of X-ray irradiation on chemotherapeutics in the plasma remain unclear. We evaluated the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation and examined the changes of protein and mRNA expression of CES1 and CYP3A1. The X-ray irradiation with 1 Gy and 5 Gy was delivered to the whole body of rats. CPT-11 at 30 and 60 mg/kg, respectively, was intravenously infused 24 h after irradiation. CPT-11 was determined by RP-HPLC in plasma. ELISA and PCR were used to analyze the protein and mRNA expression of CES1 and CYP3A1, respectively. Compared with control rats, the X-ray irradiation decreased the AUC of CPT-11 (30 mg/kg) by 15.6% at 1 Gy and 39.0% at 5 Gy and increased the CL by 60.0% at 5 Gy. The X-ray irradiation could also decrease the AUC of CPT-11 (60 mg/kg) and increase the CL. In addition, the protein and mRNA expression of CES1 and CYP3A1 were increased significantly in rats after irradiation. This study found significant changes in the pharmacokinetics of CPT-11 in rats after exposure to X-ray irradiation, and they might be due to significant increases in the expressions of CYP3A1 and CES1. The pharmacokinetics of CPT-11 should be rechecked, and the optimal CPT-11 dose should be reevaluated during concurrent chemoradiation therapy.