Biopharmaceutics & Drug Disposition最新文献_第10页

Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk 基于生理的药代动力学模型预测乳中乳腺癌耐药蛋白底物的药物浓度

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-20 DOI: 10.1002/bdd.2335

Tao Zhang, Peng Zou, Yingsi Fang, Yanyan Li

{"title":"Physiologically based pharmacokinetic model to predict drug concentrations of breast cancer resistance protein substrates in milk","authors":"Tao Zhang, Peng Zou, Yingsi Fang, Yanyan Li","doi":"10.1002/bdd.2335","DOIUrl":"10.1002/bdd.2335","url":null,"abstract":"Many mothers need to take some medications during breastfeeding, which may carry a risk to breastfed infants. Thus, determining the amount of a drug transferred into breast milk is critical for risk–benefit analysis of breastfeeding. Breast cancer resistance protein (BCRP), an efflux transporter which usually protects the body from environmental and dietary toxins, was reported to be highly expressed in lactating mammary glands. In this study, we developed a mechanistic lactation physiologically based pharmacokinetic (PBPK) modeling approach incorporating BCRP mediated transport kinetics to simulate the concentration–time profiles of five BCRP drug substrates (acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin) in nursing women’s plasma and milk. Due to the lack of certain physiological parameters and scaling factors in nursing women, we combine the bottom up and top down PBPK modeling approaches together with literature reported data to optimize and determine a set of parameters that are applicable for all five drugs. The predictive performance of the PBPK models was assessed by comparing predicted pharmacokinetic profiles and the milk-to-plasma (M/P) ratio with clinically reported data. The predicted M/P ratios for acyclovir, bupropion, cimetidine, ciprofloxacin, and nitrofurantoin were 2.48, 3.70, 3.55, 1.21, and 5.78, which were all within 1.5-fold of the observed values. These PBPK models are useful to predict the PK profiles of those five drugs in the milk for different dosing regimens. Furthermore, the approach proposed in this study will be applicable to predict pharmacokinetics of other transporter substrates in the milk.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"221-232"},"PeriodicalIF":2.1,"publicationDate":"2022-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10487429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Prediction of basic drug exposure in milk using a lactation model algorithm integrated within a physiologically based pharmacokinetic model 利用基于生理的药代动力学模型集成的哺乳模型算法预测牛奶中的基本药物暴露

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-09 DOI: 10.1002/bdd.2334

Amita Pansari, Muhammad Faisal, Masoud Jamei, Khaled Abduljalil

{"title":"Prediction of basic drug exposure in milk using a lactation model algorithm integrated within a physiologically based pharmacokinetic model","authors":"Amita Pansari, Muhammad Faisal, Masoud Jamei, Khaled Abduljalil","doi":"10.1002/bdd.2334","DOIUrl":"10.1002/bdd.2334","url":null,"abstract":"Medication use during breastfeeding can be a matter of concern due to unintended infant exposure to drugs through breast milk. The available information relating to the safety of most medications is limited and may vary. More precise information is needed regarding the safety to the newborn or infants of the medications taken by the mother during breastfeeding. Physiologically based Pharmacokinetic Model (PBPK) approaches can be utilized to predict the drug exposure in the milk of breastfeeding women and can act as a supporting tool in the risk assessment of feeding infants. This study aims to assess the predictive performance of an integrated ‘log transformed phase-distribution’ lactation model within a PBPK platform. The model utilizes the physicochemical properties of four basic drugs, namely tramadol, venlafaxine, fluoxetine, and paroxetine, and analyses the milk compositions to predict the milk-to-plasma (M/P) ratio. The M/P prediction model was incorporated within the Simcyp Simulator V20 to predict the milk exposure and to estimate the likely infant dose for these drugs. The PBPK models adequately predicted the maternal plasma exposure, M/P ratio, and the infant daily dose to within two-fold of the clinically observed values for all four compounds. Integration of the lactation model within PBPK models facilitates the prediction of drug exposure in breast milk. The developed model can inform the design of lactation studies and assist with the neonatal risk assessment after maternal exposure to such environmental chemicals or basic drugs which diffuse passively into the milk.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"201-212"},"PeriodicalIF":2.1,"publicationDate":"2022-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33493629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

The role of the efflux transporter, P-glycoprotein, at the blood–brain barrier in drug discovery 血脑屏障外排转运蛋白p -糖蛋白在药物发现中的作用

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-05 DOI: 10.1002/bdd.2331

Benoit Cox, Johan Nicolaï, Beth Williamson

{"title":"The role of the efflux transporter, P-glycoprotein, at the blood–brain barrier in drug discovery","authors":"Benoit Cox, Johan Nicolaï, Beth Williamson","doi":"10.1002/bdd.2331","DOIUrl":"10.1002/bdd.2331","url":null,"abstract":"The blood–brain barrier (BBB) expresses a high abundance of transporters, particularly P-glycoprotein (P-gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P-gp at the BBB in drug discovery and development. We highlight the differences in P-gp expression and protein levels across species but the limited observations of species-specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P-gp for several neurological disorders and ageing and exemplify several disease-specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS-related drug-drug interactions due to the inhibition or induction of P-gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P-gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 1","pages":"113-126"},"PeriodicalIF":2.1,"publicationDate":"2022-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9494138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study 依多沙班和低剂量环孢素对出血和抗凝指标的评价:一个病例系列研究

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-04 DOI: 10.1002/bdd.2332

Toshinori Hirai, Yuri Shinogi, Makoto Ikejiri, Tomohiro Murata, Takuya Iwamoto

{"title":"Evaluation of bleeding and anticoagulation markers by edoxaban and low-dose cyclosporine: A case series study","authors":"Toshinori Hirai, Yuri Shinogi, Makoto Ikejiri, Tomohiro Murata, Takuya Iwamoto","doi":"10.1002/bdd.2332","DOIUrl":"10.1002/bdd.2332","url":null,"abstract":"It was reported that high-dose cyclosporine at 500 mg daily increases edoxaban exposure. We investigated whether cyclosporine <500 mg daily leads to edoxaban-induced bleeding in the clinical setting. This case series study included patients receiving edoxaban and cyclosporine at Mie University Hospital. The outcomes were bleeding and anticoagulant markers, including activated partial thromboplastin time (APTT), prothrombin time (PT), and the international normalized ratio of prothrombin time (PT-INR). We examined the genotypes of cytochrome P450 3A5 (CYP3A5), multidrug resistance 1 (ABCB1), and solute carrier organic anion transporter 1B1 (SLCO1B1). Trends in anticoagulant markers were analyzed. Thirteen patients received edoxaban (standard dose; n = 3 and reduced dose; n = 10) and cyclosporine (1.94 ± 1.42 mg/kg). A bleeding event occurred in one patient receiving a standard dose of edoxaban plus cyclosporine of 25 mg daily (HAS-BLED score of 2 and genotypes; CYP3A5*3/*3, ABCB1 3435CT, and SLCO1B1*1a/*1b). After edoxaban treatment, anticoagulant markers were prolonged (APTT; 27.95 ± 3.64 s vs. 31.11 ± 3.90 s, p < 0.001, PT; 11.53 ± 1.01 s vs. 13.03 ± 0.98 s, p = 0.002, PT-INR; 0.98 ± 0.09 vs. 1.11 ± 0.11, p = 0.007). In summary, the genotypes of CYP3A5, ABCB1, and SLCO1B1 and the dosage of edoxaban may affect the risk of bleeding by edoxaban when co-administered with cyclosporine, even at low doses.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"192-200"},"PeriodicalIF":2.1,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33487342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells 抑胆药对人肝癌HepaRG细胞小管和窦型牛磺胆酸外排的抑制作用

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-10-04 DOI: 10.1002/bdd.2333

Marc Le Vée, Amélie Moreau, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel

{"title":"Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells","authors":"Marc Le Vée, Amélie Moreau, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel","doi":"10.1002/bdd.2333","DOIUrl":"10.1002/bdd.2333","url":null,"abstract":"HepaRG cells are highly-differentiated human hepatoma cells, which are increasingly recognized as a convenient cellular model for in vitro evaluation of hepatic metabolism, transport, and/or toxicity of drugs. The present study was designed to evaluate whether HepaRG cells can also be useful for studying drug-mediated inhibition of canalicular and/or sinusoidal hepatic efflux of bile acids, which constitutes a major mechanism of drug-induced liver toxicity. For this purpose, HepaRG cells, initially loaded with the bile acid taurocholate (TC), were reincubated in TC-free transport assay medium, in the presence or absence of calcium or drugs, before analysis of TC retention. This method allowed us to objectivize and quantitatively measure biliary and sinusoidal efflux of TC from HepaRG cells, through distinguishing cellular and canalicular compartments. In particular, time-course analysis of the TC-free reincubation period of HepaRG cells, that is, the efflux period, indicated that a 20 min-efflux period allowed reaching biliary and sinusoidal excretion indexes for TC around 80% and 60%, respectively. Addition of the prototypical cholestatic drugs bosentan, cyclosporin A, glibenclamide, or troglitazone during the TC-free efflux phase period was demonstrated to markedly inhibit canalicular and sinusoidal secretion of TC, whereas, by contrast, incubation with the noncholestatic compounds salicylic acid or flumazenil was without effect. Such data therefore support the use of human HepaRG cells for in vitro predicting drug-induced liver toxicity (DILI) due to the inhibition of hepatic bile acid secretion, using a biphasic TC loading/efflux assay.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 6","pages":"265-271"},"PeriodicalIF":2.1,"publicationDate":"2022-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/18/ae/BDD-43-265.PMC10092305.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9650970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Estimation of fraction of drug metabolism by a single UDP-glucuronosyl transferase enzyme using relative expression factor 用相对表达因子估计单udp -葡萄糖醛基转移酶的药物代谢分数

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-09-23 DOI: 10.1002/bdd.2330

Tomoyo Honda, Wataru Obuchi, Yumi Nishiya, Takahiro Shibayama, Kengo Watanabe, Nobuaki Watanabe

{"title":"Estimation of fraction of drug metabolism by a single UDP-glucuronosyl transferase enzyme using relative expression factor","authors":"Tomoyo Honda, Wataru Obuchi, Yumi Nishiya, Takahiro Shibayama, Kengo Watanabe, Nobuaki Watanabe","doi":"10.1002/bdd.2330","DOIUrl":"10.1002/bdd.2330","url":null,"abstract":"The estimation of the contributions of UDP-glucuronosyl transferase (UGT) isoforms to the overall metabolism still suffers from technical difficulties due to limited information on enzyme levels in recombinant systems and specific inhibitors, unlike the case for cytochrome P450s (CYPs). The protein expression levels of UGT in both recombinant system microsomes (RM) and human liver microsomes (HLM) were quantified using liquid chromatography-tandem mass spectrometry, and the relative expression factor (REF) value of HLM to recombinant microsomes was estimated to evaluate the fractions of drug metabolism by a single UGT enzyme (fmUGT) of UGT substrates. The REF values of UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 were 0.228, 0.0714, 0.0665, 0.420, 0.118, and 0.0442, respectively. fmUGTs in HLM were estimated for several typical UGT substrates utilizing these values and metabolic clearances in RM. These values were comparable to the reported values estimated by various methods. This study provided useful information on REF values, which promote a robust estimation of fmUGT values for UGT substrates when evaluating the contribution of UGT isoforms to total metabolic clearance.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"213-217"},"PeriodicalIF":2.1,"publicationDate":"2022-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33479253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line SLC16A1/MCT1和SLC16A3/MCT4参与l-乳酸在肝癌细胞系中的转运

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-09-14 DOI: 10.1002/bdd.2329

Yuto Mukai, Atsushi Yamaguchi, Tomoya Sakuma, Takanobu Nadai, Ayako Furugen, Katsuya Narumi, Masaki Kobayashi

{"title":"Involvement of SLC16A1/MCT1 and SLC16A3/MCT4 in l-lactate transport in the hepatocellular carcinoma cell line","authors":"Yuto Mukai, Atsushi Yamaguchi, Tomoya Sakuma, Takanobu Nadai, Ayako Furugen, Katsuya Narumi, Masaki Kobayashi","doi":"10.1002/bdd.2329","DOIUrl":"10.1002/bdd.2329","url":null,"abstract":"Fourteen isoforms of the monocarboxylate transporter (MCT) have been reported. Among the MCT isoforms, MCT1, MCT2, and MCT4 play a role in l-lactate/proton cotransport and are involved in the balance of intracellular energy and pH. Therefore, MCT1, MCT2, and MCT4 are associated with energy metabolism processes in normal and pathological cells. In the present study, we evaluated the expression of MCT1, MCT2, and MCT4 and the contribution of these three MCT isoforms to l-lactate uptake in hepatocellular carcinoma (HCC) cells. In HepG2 and Huh-7 cells, l-lactate transport was pH-dependent, which is characteristic of MCT1, MCT2, and MCT4. Furthermore, l-lactate uptake was selectively inhibited by MCT1 and MCT4 inhibitors in HepG2 and Huh-7 cells. Kinetic analysis of HepG2 cells demonstrated that l-lactate uptake was biphasic. Although the knockdown of MCT1 and MCT4 in the HepG2 cells decreased the uptake of l-lactate, the knockdown of MCT2 had no effect on the uptake of l-lactate. Consequently, we concluded that both MCT1 and MCT4 were involved in the transport of l-lactate in HepG2 and Huh-7 cells at pH 6.0. In contrast, PXB-cells, freshly isolated hepatocytes from humanized mouse livers, showed lower MCT4 expression and l-lactate uptake at pH 6.0 compared to that in HCC cell lines. In conclusion, MCT4, which contributes to l-lactate transport in HCC cells, is significantly different in HCC compared to normal hepatocytes, and has potential as a target for HCC treatment.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"183-191"},"PeriodicalIF":2.1,"publicationDate":"2022-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40357572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Changes in uridine 5′-diphospho-glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid 组蛋白去乙酰化酶抑制剂丙戊酸对尿苷5′-二磷酸葡萄糖醛酸基转移酶1A6表达的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-08-23 DOI: 10.1002/bdd.2328

Yukiko Sakakibara, Ayaka Kojima, Yuki Asai, Masayuki Nadai, Miki Katoh

{"title":"Changes in uridine 5′-diphospho-glucuronosyltransferase 1A6 expression by histone deacetylase inhibitor valproic acid","authors":"Yukiko Sakakibara, Ayaka Kojima, Yuki Asai, Masayuki Nadai, Miki Katoh","doi":"10.1002/bdd.2328","DOIUrl":"10.1002/bdd.2328","url":null,"abstract":"Valproic acid (VPA) is well-known as a histone deacetylase (HDAC) inhibitor. It has been reported that HDAC inhibitors enhance basal and aryl hydrocarbon receptor (AhR) ligand-induced aryl hydrocarbon receptor-responsive gene expression. Other studies suggested that HDAC inhibition might significantly activate the NF-E2-related factor-2 (Nrf2). Moreover, VPA activates mitogen-activated protein kinases (MAPKs). MAPK pathways regulate Nrf2 transactivation domain activity. Uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A6 is one of the important isoforms to affect drug pharmacokinetics. UGT1A6 gene is regulated transcriptionally by AhR and Nrf2. The present study aimed to investigate whether UGT1A6 expression was changed by VPA and to elucidate the mechanism of the alteration. Following VPA treatment for 72 h in Caco-2 cells, UGT1A6 mRNA was increased by 7.9-fold. Moreover, UGT1A6 mRNA was increased by other HDAC inhibitors, suggesting that HDAC inhibition caused the UGT1A6 mRNA induction. AhR and Nrf2 proteins in the nucleus of Caco-2 cells were increased by 1.5- and 1.7-fold, respectively, following the VPA treatment. However, VPA treatment did not activate the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways in Caco-2 cells. In conclusion, we observed that VPA induced UGT1A6 mRNA expression via AhR and Nrf2 pathways, but not via the ERK or JNK pathways.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 5","pages":"175-182"},"PeriodicalIF":2.1,"publicationDate":"2022-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40721462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats 陈年大蒜和银杏叶提取物对索非布韦大鼠药动学的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-08-17 DOI: 10.1002/bdd.2326

Abanoub K. Wasef, Sara A. Wahdan, Noha M. Saeed, Ebtehal El-Demerdash

{"title":"Effects of aged garlic and ginkgo biloba extracts on the pharmacokinetics of sofosbuvir in rats","authors":"Abanoub K. Wasef, Sara A. Wahdan, Noha M. Saeed, Ebtehal El-Demerdash","doi":"10.1002/bdd.2326","DOIUrl":"10.1002/bdd.2326","url":null,"abstract":"Sofosbuvir is a direct acting antiviral (DAA) approved for the treatment of hepatitis C virus (HCV). Sofosbuvir is a substrate of P-glycoprotein (P-gp). For this reason, inhibitors, or inducers of intestinal P-gp may alter the plasma concentration of sofosbuvir and increase or decrease its efficacy causing a significant change in its pharmacokinetic parameters. The purpose of the study was to evaluate the pharmacokinetic interaction between either aged garlic or ginkgo biloba extracts with sofosbuvir through targeting P-gp as well as possible toxicities in rats. Rats were divided into four groups and treated for 14 days with saline, verapamil (15 mg/kg, PO), aged garlic extract (120 mg/kg, PO), or ginkgo biloba extract (25 mg/kg, PO) followed by a single oral dose of sofosbuvir (40 mg/kg). Validated LC-MS/MS was used to determine sofosbuvir and its metabolite GS-331007 in rat plasma. Aged garlic extract caused a significant decrease of sofosbuvir AUC(0−t) by 36%, while ginkgo biloba extract caused a significant increase of sofosbuvir AUC(0−t) by 11%. Ginkgo biloba extract exhibited a significant increase of the sofosbuvir t1/2 by 60%, while aged garlic extract significantly increased the clearance of sofosbuvir by 63%. The pharmacokinetic parameters of GS-331007 were not affected. The inhibitory action of ginkgo biloba on P-gp and the subsequent increase in the sofosbuvir plasma concentration did not show a significant risk of renal or hepatic toxicity. Conversely, although aged garlic extracts increased intestinal P-gp expression, they did not alter the Cmax and Tmax of sofosbuvir and did not induce significant hepatic or renal toxicities.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"152-162"},"PeriodicalIF":2.1,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40619639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation ABCB1基因变异对非瓣膜性房颤患者利伐沙班药代动力学和出血事件的影响

IF 2.1 4区医学

Biopharmaceutics & Drug Disposition Pub Date : 2022-08-08 DOI: 10.1002/bdd.2327

Dan Zhang, Wei Qin, Wenwen Du, Xiaoxing Wang, Wenqian Chen, Pengmei Li

{"title":"Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation","authors":"Dan Zhang, Wei Qin, Wenwen Du, Xiaoxing Wang, Wenqian Chen, Pengmei Li","doi":"10.1002/bdd.2327","DOIUrl":"10.1002/bdd.2327","url":null,"abstract":"Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study. Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (Cmax/D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban Cmax/D than non-carriers. Logistic regression showed that rivaroxaban Cmax/D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban Cmax/Dose and the incidence of hemorrhage events significantly.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 4","pages":"163-171"},"PeriodicalIF":2.1,"publicationDate":"2022-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40680160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1