ABSTRACT
Drug metabolism and pharmacokinetics (DMPK) are the science to study the process of drug absorption, distribution, metabolism and excretion. It is very important to evaluate the characteristics of DMPK for the early development of drugs and the later clinical precision medication. The innovative construction of DMPK models promotes the development and improvement of drug evaluation system. Based on our research results, this review summarized the latest progress and application of innovative DMPK models, focusing on the following two aspects: (1) CRISPR/Cas9 gene editing rat models, including Cyp2e1
ABSTRACT
Physiologically based pharmacokinetic (PB-PK) model simulates the circulation of blood flow in systemic organs by using mathematical model to quantitatively describe the behavior characteristics of drugs in the body. The application of PB-PK model to special population to predict the pharmacokinetic behavior of drugs in special populations can provide support for clinical rational drug use. In recent years, chronic liver disease has gradually become an important health problem. Due to the impairment of patients' liver function, the disposal process of drug in vivo will change to some extent. Therefore, it is necessary to evaluate the impact of liver dysfunction on the drug absorption, distribution, metabolism, elimination (ADME) in order to ensure the safety and effectiveness of drug use. PB-PK model can accurately determine the ADME process of drugs in patients according to the level of liver function, and play an important role in guiding clinical rational drug use. This review will start from the impact of liver function on the process of drug ADME, summarize and discuss how PB-PK model can build a model according to the physiological and pathological changes of patients with liver dysfunction for more accurate extrapolation prediction.
ABSTRACT
As a first generation tyrosine kinase inhibitor, imatinib is the gold standard drug for the clinical treatment of chronic myelog-enous leukemia. However, interindividual differences in resistance and response to imatinib have been widely observed. In vivo and in vitro studies have confirmed that ATP-binding cassette transporters, organic cation transporters, and organic anion transporting poly-peptides have a large effect on imatinib pharmacokinetics and pharmacodynamics. In addition, the gene polymorphisms of drug trans-porters can directly or indirectly influence the intracellular concentration of imatinib, resulting in differences in treatment efficacy among chronic myelogenous leukemia patients. This review profiles the effect of drug transporter gene polymorphisms on susceptibili-ty to imatinib in chronic myelogenous leukemia so as to provide reference to further clinical researches.
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
Objective: To explore the effect of arecoline hydrobromide (AH) on the expression of rat hepatic and renal transporters. Methods: The effect of AH on the mRNA expression of 13 hepatic and renal transporters was studied after orally giver AH (0.8, 4, and 20 mg/kg/d) to rats for 21 d. Results: The results from the real-time PCR indicated that, AH treatment at low dose significantly decreased the mRNA levels of hepatic MRP2 and MDR1A, while significantly increased renal MRP5 mRNA level. On the other hand, AH treatment at high dose significantly inhibited the mRNA expression of hepatic OCT2, OAT2, OCTN2, OATP1A1, OATP1A4, OATP2B1, MRP2, and MDR1A, as well as renal MRP2, BCRP, and MDR1A. However, the mRNA expression of renal OCTN2, OATP1A1, OATP1A4, and MRP5 were significantly up-regulated following the treatment of high dose of AH. And the AH-induced effect on the above transporters was dose dependent in some extent. Conclusion: Due to the drug interaction caused by the alteration in expression and function of hepatic and renal transporters, it is suggested that the betel nut addicts should be paid more attention in case of adverse drug interactions.
ABSTRACT
The radiation is regarded as the fourth biggest pollution following the water, air and noise pollution, which generates a broad impact on human physiology and healthy. The radiation mainly comes from medical rays, industrial rays, nuclear wastes and atmospheric ultraviolet rays. The universality makes people pay more and more attention to the damage effect and mechanism of radiation. The radiation is divided into ionizing and non-ionizing radiation. It is a good idea to study the effect of ionizing and non-ionizing radiation on drug's metabolism, which may give a guidance to clinical medication to avoid adverse reactions and to support personalized medicine. This article reviews the effect of ionizing radiation (γ-rays, X-rays, uranium and cesium) and non-ionizing radiation (ultraviolet rays) on drug metabolism, their impact on metabolic characteristics of some drugs and the impact on expression of enzymes and transporters in drug metabolism, which is conducted with a focus on clinical significance.
ABSTRACT
The disposition of drug in vivo is subjected to a series of biotransformation and transport, depending on the involvement of drug-metabolizing enzymes and transporters.However, the individual capacity varies when metabolizing and transporting the same drug, and pharmacogenomics has trouble in completely explaining the differences.microRNA, a key aspect of epigenetic modifications, is a powerful complement to traditional genetics.Emerging evidences have confirmed that drug-metabolizing enzymes and transporters be controlled by different microRNAs, and the same microRNA also regulates several drug-metabolizing enzymes or/and transporters simultaneously.All of these researches infer that microRNAs are likely to realize the comprehensive macro-regulation of gene expression.The further study of microRNAs maybe a suitable point to research the interindividual variability in disposition of drugs, and it provides a theoretical basis for rational use of drug and individualized medicine.
ABSTRACT
In recent years,the research on drag transporters has made great progress,more and more transporters have been found and studied,and they have shown important roles in the transport of drug across the cellular membrane.Various transporters,including uptake transporters and effiux transporters,have important effects on the pharmacokinetics and drug-drug interactions.Studies have shown that the process in vivo of most of the antibiotics was related to transporters and metabolizing enzymes (cytochrome P450 and CYP450).Therefore,this article summarized the latest research progress in pharmacokinetics and drug-drug interactions of transporters and CYP450,so that provides evidence for clinical rational use of antibiotics.
ABSTRACT
Zuotai and cinnabar(96%HgS) are contained in many traditional medicines. To examine their potential effects on drug metabolism genes, mice were orally given Zuotai or HgS at doses of 10, 30, 100, 300 mg•kg⁻¹ for 7 days. HgCl2(33.6 mg•kg⁻¹) was gavaged for control. Twenty-four hour later after the last administration, livers were collected, and expressions of genes related to metabolic enzymes and transporters were examined. Zuotai and HgS had no effects on major phase-1, phase-2 and transporter genes; HgCl2 increased the expressions of CYP2B10, CYP4A10, OATP1A4, UGT1A1, UGT2A3, SULT1A1, SULT2A1, MRP1, MRP3 and MRP4; expression of OATP1A1 was decreased by HgCl2, but not by Zuotai and HgS. Therefore, Zuotai and HgS have different adverse effects on drug-metabolizing genes from HgCl2.
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
Pharmacogenomics is a discipline studying the influence of genetic differences on drug effectiveness .It promises to op-timize the effect of medicine and reduce side effects .It is one of the most effective ways to predict the drug reaction in human body by using pharmacogenomics , which can achieve the goal of precision medicine .With the rapid development of the genetical test technolo-gies, the in vitro individual genome testing projects with the properties of high throughput , and measurable and low cost are better to be applied in medical practice and guiding for making individualized medicine plan .The study elucidated the progress in single nucleotide polymorphism and its clinical application , and focused on the strategic effects of pharmacogenomics on individualized treatment and gene diversity for guiding medicine .
ABSTRACT
Multidrug resistance (MDR) is the most common cause in the failure of cancer chemotherapy. Drug transporters play an important role in multidrug resistance in cancer. Activation of drug pumps which belong to ATP-binding cassette (ABC) transporters leads to the efflux of drug via cell membrane.Three subgroups of ABC transporters are involved in the transport of cytotoxic drugs.These transporters include ABCB subgroup,ABCC subgroup and ABCG subgroup. In this review,the author discussed the recent research advances in the ABC transporters associated with MDR.