ABSTRACT
Plateau environment has the characteristic of low ox-ygen and low pressure, which leads to a series of physiological changes and affects the process of drug metabolism in the body. Many factors affect the pharmacokinetic parameters, including gastric emptying, blood rheology, cardiopulmonary function, hepatorenal function, cytochrome P450 enzyme and so on. The present study focuses on drug metabolic enzymes, since drug transporter is the key factor that mediates drugs in their entrance to the body through the cell membrane, producing the curative effect. In order to provide the reference to further research on the effect of plateau hypoxia on pharmacokinetics and guide the rational use of drugs, we review in this paper the classification of the transporter, mediated drug substrates, the influence of hypoxia on expression levels of drug transporter substrates and the regulatory mechanism of drug transporter under the condition of hypoxia.
ABSTRACT
The relationship between PEPT1 (peptide transporter) and drug efficacy has drawn more and more attention in the treatment of disease. PEPT1 represents a promising strategy for improvement of drug bioavailability and an important starting point for clinical rationalization of drug selection. The effect of PEPT1 on transport and pharmacokinetics of amoxicillin was investigated under hypoxia condition at high altitude in rat. The mRNA and protein expressions of PEPT1 were increased by 36.87%, 216.21%, 577.8% and 535.9% respectively in the hypoxia group in the small intestine and kidney of rats. However, the mRNA and protein expressions of PEPT1 were reduced by 43.90% and 84.7% in the liver. Compared with the control group, the AUC, tmax, Cmax, MRT and t1/2 of amoxicillin were significantly enhanced by 312.17%, 63.04%, 110.93%, 67.11% and 16.96% respectively in the hypoxia group, while the CL was significantly decreased by 74.51%. After acute exposure to high altitude, the expressions of drug transporter PEPT1 were distinctly changed in rat tissues, which can affect the pharmacokinetics of amoxicillin.
ABSTRACT
The drug transporter play a key role in the absorption of drugs. Investigation of the changes of drug transporters in response to hypoxia will provide insight into the mechanism of drug absorption. In this study we investigated the mRNA and protein expression of the transporter P-gp after acute hypoxia, and evaluated the effects of P-gp changes on absorption of levofloxacin in the intestine. The relative expression of mRNA and protein were reduced by 50.80% and 71.30% (PP<0.05). These results suggest that hypoxia may decrease the expression of P-gp in the intestine to reduce the excretion of levofloxacin and increase the absorption.
ABSTRACT
<p><b>OBJECTIVE</b>To study the changes in the physiological parameters and gene expression of two drug efflux transporters MDR1 and MRP2 in the small intestine, liver and kidney of rats exposed to acute hypoxia.</p><p><b>METHODS</b>Eighteen Wistar rats were randomly divided into control group, hypoxia for 24 h group and hypoxia for 72 h group. Blood samples were obtained from the abdominal aorta of the rats after the exposure for analyzing the physiological indexes. The mRNA expressions of MDR1 and MRP2 were determined using Real-Time PCR, and their protein expressions were detected with enzyme-linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>The physiological parameters of the rats in hypoxia group were significantly changed compared with those in the control group. The expressions of MDR1 and MRP2 mRNA and proteins in the small intestine, liver and kidney were significantly increased in rats with hypoxic exposure than in the control rats (P<0.05 or 0.01). As the hypoxic exposure prolonged, the two transporters showed different patterns of variation in different tissues.</p><p><b>CONCLUSION</b>Acute hypoxia affects the physiological parameters and expression levels of MDR1 and MRP2, thus causing changes in the metabolism of the substrates of the transporters. These changes may play an important role in the pharmacokinetics of drugs at a high altitude.</p>