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1.
Acta Pharmaceutica Sinica B ; (6): 2973-2982, 2021.
Article in English | WPRIM | ID: wpr-922799

ABSTRACT

The 2020 Nobel Prize in Chemistry recognized CRISPR-Cas9, a super-selective and precise gene editing tool. CRISPR-Cas9 has an obvious advantage in editing multiple genes in the same cell, and presents great potential in disease treatment and animal model construction. In recent years, CRISPR-Cas9 has been used to establish a series of rat models of drug metabolism and pharmacokinetics (DMPK), such as

2.
Chinese Pharmaceutical Journal ; (24): 1512-1516, 2020.
Article in Chinese | WPRIM | ID: wpr-857584

ABSTRACT

OBJECTIVEP: To investigate the effect of flavonoids and triterpenoids on the function of organic anion transporting polypeptide 1B3. METHODS: Natural products such as flavonoids and triterpenoids are widely present in traditional Chinese medicine and daily diets. In the present study, CHO cells stably expressing OATP1B3 and its fluorescent substrate fluorescein methotrexate were employed to investigate the effect of 21 natural products on the function of OATP1B3. RESULTS: Mulberrin, glycyrrhetinic acid, glycyrrhizic acid, quercitrin, quercetin, and chrysanthemum stem-leaf flavonoids showed significant inhibitory effects on OATP1B3-mediated uptake of fluorescein methotrexate, with IC50 values being of 3.6, 3.8, 7.5, 9.0, 10.1 μmol•L-1, and 4.1 μg•mL-1, respectively. The IC50 value of glycyrrhetinic acid on OATP1B3 was comparable to its blood concentration in clinics, indicating an OATP1B3-mediated drug-drug interaction could occur. CONCLUSION: Some flavonoids and triterpenoids are OATP1B3 inhibitors. When patients take medications of OATP1B3 substrates, care should be taken to avoid coadmistration of drugs or food containing these inhibitors to circumvent the occurrence of adverse drug interactions.

3.
Article in Chinese | WPRIM | ID: wpr-855886

ABSTRACT

The physiologically based pharmacokinetic (PBPK) model, as a physiological mechanism-based model, can simulate the absorption, distribution, metabolism and excretion of drugs in the body. In recent years, it has been widely used in drug-drug interaction study, special population extrapolation, clinical trial dose selection, individualized medication and impact of different factors on the pharmacokinetic course. This review briefly describes the history and current development of PBPK model, introduces the work flow of PBPK model, and reviews its application in drug clinical study in recent years. We hope this review could provide a reference for researchers who are interested in this field.

4.
Article in Chinese | WPRIM | ID: wpr-855864

ABSTRACT

AIM: To evaluate the effects of resveratrol on five human cytochrome enzyme P450 subtypes, i.e. CYP1A2, CYP2D6, CYP2C9, CYP3A4, and CYP2C19, through a combined probe method. METHODS: We conducted a randomized controlled study in which 26 healthy male volunteers were recruited and were randomized into the resveratrol group and the placebo group. Volunteers were given oral placebo /resveratrol at a dose of 1 g each time, once daily for 14 days. Then, they took five oral probe drugs, caffeine (for CYP1A2), losartan (for CYP2D6), omeprazole (for CYP2C19), dextromethorphan (for CYP2C9), and midazolam (for CYP3A4). Blood samples at different times were collected to detect the concentration of the three probes, i.e. midazolam, caffeine and omeprazole; 0-8 h urine samples were collected to measure the metabolic rate of losartan and dextromethorphan. RESULTS:Compared with the placebo group, the AUC0-12, AUC0-∞, Cmax of caffeine in the resveratrol group was increased by 32.10% (P0.05) as compared with the placebo group. The 8 h urinary DTM/DT ratio was increased by 79.91% (P=0.003) and 8 h urinary losartan/E-3174 ratio was increased by 531.34% (P<0.001).CONCLUSION: Resveratrol significantly inhibited the enzymatic activities of CYP1A2, CYP2D6 and CYP2C9 after repeated administration, but did not significantly change the enzymatic activities of CYP3A4 and CYP2C19.

5.
Acta Pharmaceutica Sinica B ; (6): 850-860, 2020.
Article in English | WPRIM | ID: wpr-828839

ABSTRACT

Organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/3) as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells. Rat OATP1B2, encoded by the gene, is homologous to human OATP1B1/3. Although OATP1B1/3 is very important, few animal models can be used to study its properties. In this report, we successfully constructed the S knockout (KO) rat model using the CRISPR/Cas9 technology for the first time. The novel rat model showed the absence of OATP1B2 protein expression, with no off-target effects as well as compensatory regulation of other transporters. Further pharmacokinetic study of pitavastatin, a typical substrate of OATP1B2, confirmed the OATP1B2 function was absent. Since bilirubin and bile acids are the substrates of OATP1B2, the contents of total bilirubin, direct bilirubin, indirect bilirubin, and total bile acids in serum are significantly higher in KO rats than the data of wild-type rats. These results are consistent with the symptoms caused by the absence of OATP1B1/3 in Rotor syndrome. Therefore, this rat model is not only a powerful tool for the study of OATP1B2-mediated drug transportation, but also a good disease model to study hyperbilirubinemia-related diseases.

6.
Acta Pharmaceutica Sinica B ; (6): 79-90, 2020.
Article in English | WPRIM | ID: wpr-781549

ABSTRACT

Cancer cells reprogram their gene expression to promote growth, survival, proliferation, and invasiveness. The unique expression of certain uptake transporters in cancers and their innate function to concentrate small molecular substrates in cells make them ideal targets for selective delivering imaging and therapeutic agents into cancer cells. In this review, we focus on several solute carrier (SLC) transporters known to be involved in transporting clinically used radiopharmaceutical agents into cancer cells, including the sodium/iodine symporter (NIS), norepinephrine transporter (NET), glucose transporter 1 (GLUT1), and monocarboxylate transporters (MCTs). The molecular and functional characteristics of these transporters are reviewed with special emphasis on their specific expressions in cancers and interaction with imaging or theranostic agents [., I-123, I-131, I-iobenguane (mIBG), F-fluorodeoxyglucose (F-FDG) and C pyruvate]. Current clinical applications and research areas of these transporters in cancer diagnosis and treatment are discussed. Finally, we offer our views on emerging opportunities and challenges in targeting transporters for cancer imaging and treatment. By analyzing the few clinically successful examples, we hope much interest can be garnered in cancer research towards uptake transporters and their potential applications in cancer diagnosis and treatment.

7.
Article | IMSEAR | ID: sea-200161

ABSTRACT

Background: Cardiovascular disease is one of the major causes of mortality and morbidity in a developing country like India. These patient’s prescription contains multiple drugs to reduce the mortality and morbidity and they also contain drugs for treatment of co morbidities leading to polypharmacy. The main objective of the study was to identify the pattern of drug- drug interaction (DDI) in patients on cardiovascular drugs with various co existing morbidities.Methods: This study was conducted in the Department of General Medicine of a tertiary care center. Prescription of 200 patients were analysed for demographic details like gender, age, comorbidities and drugs prescribed. DDI were assessed using Micromedex software.Results: In this study, conducted on the prescription of 200 elderly patients, 13 (66%) prescription had 408 DDI, of which 158 (39%) were major, 246 (60%) were moderate and 1 (0.02%) was contraindicated and 3 (0.007%) were minor.Conclusions: It can be concluded from the present study that the risk of DDI increases with the increase in number of drugs in the prescription and there is increase in number of drugs in the prescription with the increase in number of co morbidities. The antiplatelet and anticoagulant group of drugs were responsible for majority of DDI, followed by antihypertensives and hypoglycaemic agents. Most of these DDI could be avoided with slight modification in the dosage regimen based on the pharmacokinetics and pharmacodynamics of the drug.

8.
Article in Chinese | WPRIM | ID: wpr-755363

ABSTRACT

Elderly patients have become a special concern in the management of hepatitis C .Their HCV exposure time is long and the risk of liver disease and extrahepatic complications is high .With the advent of direct antiviral drugs (DAA), the treatment of chronic hepatitis C has been significantly improved , and the cure rate of virology can be more than 90% in the elderly patients , with a high safety.However, elderly patients often have more underlying diseases and the drug use will be more complicated , resulting in drug interaction ( DDI) and increasing the challenge of treatment management.This article reviews the requirements for comprehensive evaluation of elderly patients before DAA treatment , including liver and kidney function, combined drug use and potential DDI.The monitoring of adverse events and DDI , and the countermeasures are also discussed in the article.

9.
Article in Chinese | WPRIM | ID: wpr-857577

ABSTRACT

OBJECTIVE To evaluate plasma pharmacokinetics, distribution of target organs, sedative effect and respiratory depression of sufentanil (SFTN), and dexmedetomidine (DEM) in rats, and to explore the potential drug-drug interactions between the two drugs. METHODS  Rats were intravenously injected with SFTN 20.0 μg•kg-1, DEM 25.2 μg•kg-1 and SFTN+DEM (SFTN 20.0 μg•kg-1, DEM 25.2 μg•kg-1), respectively. Plasma samples were taken at different time points (2, 5, 15, 30 min and 1, 2, 4, 6, 8 h) to determine the concentrations of SFTN and DEM using the liquid chromatography-mass spectrometry (LC-MS/MS) quantitative method established in this study. The same method was used to determine the concentrations of SFTN and DEM in plasma and brain samples taken at different time points (5, 15, 30, 60 and 120 min). Pharmacokinetic parameters were obtained by noncompartmental analysis performed using Phoenix WinNonlin 7.0 (Pharsight, California). The duration of drug-induced loss of right reflex (LORR) and respiratory function were also measured using instrument monitoring. RESULTS  An LC-MS/MS method for quantitative analysis of plasma SFTN and DEM was established and validated. The Cmax,;t1/2, and Cl ;of SFTN in SFTN group were (22.2±2.6) ug•L-1, (2.13±0.69) h and (2288±446) mL•h-1•kg-1, respectively, compared with (15.9±9.4) μg•L-1, (1.22±0.13) h and (3565±743) mL•h-1 •kg-1 in SFTN+DEM group. The Cmax, t1/2, and Cl of DEM in DEM group were (14.0±8.9) μg•L-1, (1.21±0.15) h and (4235±752) mL•h-1•kg-1, compared with (9.4±3.5) μg•L-1, (1.08±0.26) h and (4796±744) mL•h-1•kg-1 in SFTN+DEM group. The Cmax ratio of SFTN in brain and plasma of SFTN+DEM group was 0.49, which was 1.3-fold that of SFTN group (0.45). The Cmax ratio of DEM in brain and plasma of SFTN + DEM group was 16.9, which was 12-fold that of DEM group (1.42). The duration of LORR of SFTN, DEM, and SFTN+DEM groups was 370±13, 41±5 and (104±24) min, respectively, and that of SFTN+DEM group was more significantly extended than those in SFTN and DEM groups (P<0.01). Respiratory depression of SFTN+DEM group was not further aggravated compared with SFTN group, but the duration of inhibition was extended (P<0.05, P<0.01). CONCLUSION  The combination of SFTN and DEM can cause drug-drug interactions, which may promote the sedation and prolong the respiratory depression by increasing the exposure level of DEM brain tissue. In clinical application, attention should be paid to the possible drug-drug interactions or adverse reactions caused by the combination of these two drugs.

10.
Acta Pharmaceutica Sinica B ; (6): 1035-1049, 2019.
Article in English | WPRIM | ID: wpr-774924

ABSTRACT

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.

11.
Article | IMSEAR | ID: sea-199630

ABSTRACT

Background: Drug interaction occurs when presence of one drug affects the activity of another when, both are co-administered. 6-30% of adverse events (AEs) with significant hospitalizations or death are by drug-drug interactions(DDI). There is increased possibility to prevent the potential drug-drug interactions (pDDIs), if their prevalence and pattern are determined accurately before their occurrence. Hence this study aimed to evaluate the prevalence of pDDIs in ICU patients at BRIMS tertiary care hospital, Bidar.Methods: This prospective observational study included 30 patients admitted in ICU of BRIMS hospital for >24hrs of either gender, aged >18yrs. The study was conducted for a period of 3 months. Data was collected from the case records of patients on the predesigned proforma. Potential drug-drug interactions were classified based on their severity and the risk of Potential drug-drug interactions was estimated by Lexicomp, inc.version; 3.0.1.drug interact android mobile application.Results: Out of 35 patients admitted in the ICU, 30 cases were included in the study. The mean age of study population was 56.3years. The study population was exposed to a total of 330 medicines during the hospital stay with an average of 11.7 drugs per patient. The prevalence of pDDI was 93.3% (28) with an average of 9.75 pDDI per patient. According to Lexicomp drug interact android mobile application majority (63%) of pDDI were found to be moderate in their severity, 67% belonged to type C risk.Conclusions: The study showed higher prevalence of pDDI among ICU patients due to the complexity of the pharmacotherapies administered.

12.
Article in Chinese | WPRIM | ID: wpr-851600

ABSTRACT

Objective To compare the effect of Compound Wurenchun Capsule (CWC) and Wuzhi Capsule (WZC), CWC single and long-term administration on the pharmacokinetics of tacrolimus (FK506). Methods Twenty-four rats were randomly divided into FK506, CWC + FK506, WZC + FK506 and CWC7d + FK506 groups, with six rats in each group. Rats in FK506, CWC + FK506, and WZC + FK506 groups were given a single gavage with FK506, CWC + FK506, and WZC + FK506 respectively. Rats in CWC7d + FK506 group was given a multiple gavage regimen of daily CWC gavage for 6 d, CWC and FK506 on day 7. Blood sample from orbit before and after gavage at different time points (CWC7d + FK506 group before and after the last administration) were tested for FK506 blood concentration and the pharmacokinetic parameters were calculated. Results Compared with FK506 group, peak blood concentration (Cmax) and area under the curve (AUC0-t) of FK506 increased significantly (P < 0.05, 0.01), body retention time (MRT0-t) of FK506 prolonged significantly (P < 0.05, 0.01), the apparent volume of distribution (V/F) and the drug elimination rate (CL/F) of FK506 decreased significantly (P < 0.01) in WZC + FK506 and CWC + FK506 groups. Compared with WZC + FK506 group, AUC0-t of FK506 increased significantly (P < 0.01), CL/F of FK506 decreased significantly (P < 0.01) in CWC + FK506 group. Compared with CWC + FK506 group, Cmax of FK506 increased significantly (P < 0.01), time to peak blood concentration (tmax) of FK506 shortened significantly (P < 0.05), AUC0-t of FK506 increased significantly (P < 0.05), CL/F of FK506 decreased significantly (P < 0.05) in CWC7d + FK506 group. Conclusion Both CWC and WZC can increase Cmax and AUC0-t, prolong MRT0-t, reduce V/F and CL/F of FK506. CWC is better than WZC in increasing AUC0-t and inhibiting CL/F of FK506. CWC long-term administration is better than single-dose in improving Cmax, AUC0-t and reducing tmax of FK506.

13.
Article in Chinese | WPRIM | ID: wpr-811764

ABSTRACT

@#To investigate the effect of combination of schisandrin B and doxorubicin on the pharmacokinetic behavior of doxorubicin in SD rats. An LC-MS/MS method was established for the determination of doxorubicin and its main metabolite doxorubicinol in SD rats plasma. Separation was performed on Agilent Eclipse XDB-C18 column(100 mm×2. 1 mm, 3. 5 μm)using 0. 1% formic acid solution and acetonitrile as mobile phase with a liner gradient program. The ion transitions were performed under ESI position model at m/z 544. 2→397. 3(doxorubicin), m/z 546. 2→399. 2(doxorubicinol), m/z 528. 2→381. 2(daunorubicin, internal standard). Calibration curves of doxorubicin(0. 500-500 ng/mL)and doxorubicinol(0. 200-50. 0 ng/mL)showed good linear regression. The precision and accuracy met the requirements. The variation coefficient of extraction recovery and matrix effect was less than 15%. The AUC0-t of doxorubicin were(605. 69±145. 84)and(564. 53±23. 99)ng ·h/mL in alone and combined group, respectively. The AUC0-t of doxorubicinol were(26. 69±13. 41)and(29. 00±2. 78)ng ·h/mL, respectively. Results indicated that, schisandrin B had not affected the pharmacokinetic behavior of doxorubicin in SD rats.

14.
Chinese Journal of Hepatology ; (12): 481-488, 2018.
Article in Chinese | WPRIM | ID: wpr-810053

ABSTRACT

Approved direct-acting antiviral agents (DAA ) in chronic hepatitis C were introduced. Metabolism and pharmacokinetics data of DAAs were analyzed. Comorbidity and concomitant medications of chronic hepatitis C (CHC) patients were extracted from Chinese Health Insurance database. Drug-drug interactions (DDIs) were calculated by integrated above data and confirmed by using Liverpool DDI website. Based on those data, experts propose consensus on management of drug-drug interaction with direct-acting antiviral agents in chronic hepatitis C, including pre-treatment, on-treatment, and post-treatment.

15.
Chinese Journal of Hepatology ; (12): 481-488, 2018.
Article in Chinese | WPRIM | ID: wpr-691172

ABSTRACT

Approved direct-acting antiviral agents (DAA ) in chronic hepatitis C were introduced. Metabolism and pharmacokinetics data of DAAs were analyzed. Comorbidity and concomitant medications of chronic hepatitis C (CHC) patients were extracted from Chinese Health Insurance database. Drug-drug interactions (DDIs) were calculated by integrated above data and confirmed by using Liverpool DDI website. Based on those data, experts propose consensus on management of drug-drug interaction with direct-acting antiviral agents in chronic hepatitis C, including pre-treatment, on-treatment, and post-treatment.

16.
China Pharmacist ; (12): 264-267, 2018.
Article in Chinese | WPRIM | ID: wpr-705504

ABSTRACT

Objective:To provide basis for the rational use of valproic acid(VPA) in the patients with epilepsy through the analy-sis on the therapeutic monitoring data. Methods:The VPA plasma concentration and the other related information of 233 cases were analyzed retrospectively. Results:The total daily dose of VPA increased with age (P<0.05) in children group. Compared with that in adults group (19-50 years old),the target rate of VPA concentration was significantly higher in children group(4-14 years old) (P<0.001). VPA had similar antiepileptic effect in children and adults. Oral solution was the main dosage form for children and con-ventional tablets for adults. Children had higher target rate of VPA concentration than adults (P<0.05). Compared with the group with VPA alone,VPA combined with enzyme inducers such as carbamazepine,phenobarbital and phentoin significantly decreased the target rate of VPA concentration(P<0.001). Moreover,VPA combined with phenobarbital significantly decreased the total daily dose of VPA (P<0.05). Conclusion:With great inter-individual variance,VPA plasma concentration is associated with efficacy and side effects. Monitoring of VPA plasma concentration is useful to the individualized treatment of VPA.

17.
Article in English | WPRIM | ID: wpr-728590

ABSTRACT

Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in C(max) of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.


Subject(s)
Area Under Curve , Caffeine , Ciprofloxacin , Computer Simulation , Drug Discovery , Humans , In Vitro Techniques , Permeability , Pharmacokinetics , Solubility , Tissue Distribution
18.
Drug Evaluation Research ; (6): 1216-1222, 2017.
Article in Chinese | WPRIM | ID: wpr-664700

ABSTRACT

Transporters are a class of functional membrane proteins which are broadly expressed in the kidney and play a vital role in the reabsorption and secretion of many endogenous and xenobiotic compounds by the kidney.The renal proximal tubule is the primary site of transporter-mediated active transport for many drugs,including organic anion drugs,organic cation drugs and peptide drugs.Transporter-mediated drug-drug interactions may occur in the kidney when some drugs are co-administration.In this review,we focus on the location and function of major transporters in the kidney and summarize their vital role in renal drug elimination.

19.
Drug Evaluation Research ; (6): 1223-1228, 2017.
Article in Chinese | WPRIM | ID: wpr-664698

ABSTRACT

Drug transporters and drag metabolic enzymes are crucial factors in the process of drug treatment.Rhein,as the main active component of traditional Chinese medicine rhubarb,has a wide range of pharmacological activities.Previous studies have shown that rhein is closely related to drug transporters and metabolic enzymes,and can directly activate or inhibit the functions of a variety of transporters and their protein expression.Furthermore,rhein can inhibit the function and protein expression of cytochrome P450 (CYP450),a drug metabolizing enzyme.Thus,when rhein is combined with other drugs,the drug-drug interaction (DDI) may occur based on pharmacokinetic.This paper focuses on the distribution of drug transporters,metabolic enzymes,and the effects of rhein on transporters and metabolic enzymes.

20.
China Pharmacy ; (12): 1924-1927, 2017.
Article in Chinese | WPRIM | ID: wpr-607951

ABSTRACT

OBJECTIVE: To provide reference for reducing disadvantageous drug-drug interaction(DDI)and avoiding adverse drug event(ADE). METHODS: The patients aged more than 65 were selected from cardiovascular department in our hospital dur-ing Jun. 2015-Mar. 2016. The influential factors for potential DDI(PDDI)-induced ADE were analyzed. The relationship of related factors with PDDI-induced ADE was analyzed by multivariate Logistic regression analysis. RESULTS:A total of 328 patients were included,involving 257 PDDI patients,and totally 452 cases of PDDI (including 247 cases of mild PDDI,149 cases of general PDDI and 56 cases of severe PDDI). The age,the number of drugs used simultaneously,Ccr and liver function (Child-Pugh score)were related to the occurrence of PDDI-induced ADE(P<0.01). CONCLUSIONS:For PDDI-induced ADE,the risk evalua-tion can be conducted for a series of factors,including age,the number of drugs used simultaneously,Ccr and liver function. For high-risk patients,intervene should be conducted in advance to reduce the risk of ADE.

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