EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Wenyan Li,Zheng Jiao,Yanhui Liu,Jiacheng Yao,Guodong Li,Jing Dong
Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro . Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC 50 >500 μM). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC 50 , I max,u /IC 50 ) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro , no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.
研究领域:
药理学
·
分子生物学
·
临床医学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 4
·1995
·
IF 4.6
Aijie Zhang,Fanlong Yang,Yang Yuan,Cai Li,Xiaokui Huo,Jing Liu,Shenzhi Zhou,Wei Li,Na Zhang,Jianfeng Liu,Shiqi Dong,Huirong Fan,Ying Peng,Jiang Zheng
Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration–time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not byp-aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3.Keywords:Y101;entecavir;renal excretion;organic anion transporters;drug-drug interaction
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
·
2017
·Vol. 38
·期 9
·526-534
·
IF 2.091
Liping Li,Yayun Weng,Wei Wang,Mengru Bai,Hongmei Lei,Hui Zhou,Huidi Jiang
Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells ( m PRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.
研究领域:
药理学
·
肾病学
·
药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2019
·
IF 3.414
Peter Yaro,Jing Nie,Mingcheng Xu,Kui Zeng,Houhong He,Jianbiao Yao,Ruwei Wang,Su Zeng
Ethnopharmacological relevance The major terpene lactones of ginkgo biloba extract (GBE) include ginkgolide A , B, C and bilobalide are used for the protection of cardiovascular, cerebrovascular and neurodegenerative diseases. Terpene lactones are orally bioavailable and predominantly eliminated via the renal pathway. However, information on the transporters involved in the pharmacokinetics (PK) and renal excretion of terpene lactones is limited. Aim of the study The objective of this study is to assess the role of OAT1/3 which are important transporters in the human kidney in the PK and renal excretion ginkgolide A, B, C and bilobalide. Materials and methods Uptake of ginkgolide A, B, C and bilobalide in Madin-Darby Canine Kidney (MDCK) and human embryonic kidney 293 (HEK293) cells overexpressing OAT1 or OAT3, respectively were studied. To verify the result from in vitro cell models, the studies on PK, kidney accumulation and urinary excretion of ginkgolide A, B, C and bilobalide were carried out in rats. Results The result showed that ginkgolide A, B, C and bilobalide are low-affinity substrates of OAT1/3. Following co-administration with probenecid , a typical inhibitor of OAT1/3, the rat plasma concentrations of ginkgolide A, B, C and bilobalide increased significantly. AUC showed a significant increase in the probenecid-treated rats compared to control rats (893.48 vs. 1123.85, 314.91 vs. 505.74, and 2724.97 vs. 3096.40 μg/L*h for ginkgolide A, B and bilobalide, respectively), while the clearance of these compounds significantly decreased. The accumulation of ginkgolide A, B and bilobalide in the kidney of the probenecid-treated rats was reduced by 1.8, 2.4, and 1.5-fold, respectively; further reducing the cumulative urinary recovery of these compounds. Conclusion The findings indicated that ginkgolide A, B and bilobalide are excreted via OAT1/3-mediated transport in the kidney and OAT1/3 inhibitor significantly influence the PK ginkgolides and bilobalide.
研究领域:
药理学
·
民族药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Bulletin
·
2022
·
IF 20.577
Shaohua Qu,Qian Jia,Zheng Li,Zhongliang Wang,Li Shang
Near-infrared II (NIR-II) fluorescent nanoprobes hold great potential for biomedical applications. Elucidating the relationship between surface properties of NIR-II nanoprobes and their biological behaviors is particularly important for future probe design and their performance optimization. Despite the rapid development of NIR-II nanoprobes, the distinct role of surface chirality on their biological fates has rarely been exploited. Herein, chiral NIR-II fluorescent Ag 2 S quantum dots (QDs) are synthesized to investigate the relationship between their chirality and biological functions at both in vitro and in vivo levels. D- / L -Ag 2 S QDs exhibit significant differences on their interactions with serum proteins, which further affect the cellular uptake. As a result, D -Ag 2 S QDs can be internalized with higher efficiency (over 2-fold) than that of L -Ag 2 S QDs. Moreover, in vivo studies reveal that the chirality determines the primary localization of these chiral QDs, where a more efficient renal elimination of D -Ag 2 S QDs was observed than that of L -Ag 2 S QDs. Importantly, D -Ag 2 S QDs show preferential accumulation in tumor region than that of L -Ag 2 S QDs in orthotopic kidney tumor model, which points out a new avenue of enhancing targeting capabilities of nanoprobes by engineering their surface chirality.
研究领域:
生物医学工程
·
纳米技术
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Yongqi Yang,Qiaohui Chen,Xiaohong Ying,Ziyu Wu,Wan Zeng,Chenxi Miao,Yayun Nan,Qiong Huang,Kelong Ai
Acute kidney injury (AKI) has an alarmingly high annual incidence. Heterogeneous AKI shares a common pathological hallmark—excessive reactive oxygen species (ROS), primarily generated from damaged proximal tubular epithelial cells (PTECs). Toxic ROS overload triggers mitochondrial dysfunction and excessive inflammation, initiating pathological crosstalk and vicious cycles that exacerbate AKI progression. However, many emerging preclinical therapeutic strategies or nanotechnologies face obstacles, including poor biocompatibility, inadequate targeting, and/or complex assembly, which hinder drug delivery and clinical translation. To address these limitations, fully-biocompatible tantalum-based antioxidant nanoshields (fTANS) with megalin (PTECs receptor)-mediated active targeting have been developed. fTANS combine the elegant delivery capability from albumin coating with the superior ROS-scavenging efficiency from reduced tantalum. fTANS traverse the glomerular filtration barrier with ultra-small particle size and actively internalize into PTECs via the affinity between megalin and albumin, sequentially targeting mitochondria due to their mitochondrial affinity. By modulating ROS signals, fTANS effectively preserve mitochondria, thereby limiting cytochrome c -induced apoptosis and mitochondrial DNA-triggered cGAS/STING-mediated sterile inflammation, ultimately leading to effective treatment in AKI models. Following treatment, fTANS are cleared via renal excretion without observable toxicity, exhibiting remarkable biocompatibility. Collectively, this work represents a compelling advancement in targeted antioxidant nanomedicine, offering a promising avenue for AKI treatment.
研究领域:
纳米医学
·
肾脏药理学
·
抗氧化治疗
·
线粒体生物学
·
靶向药物递送
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Medicine
·
2020
·Vol. 15
·期 1
·1-18
·
IF 2.96
Qin Zifei,Jia Mengmeng,Yang Jing,Xing Han,Yin Zhao,Yao Zhihong,Zhang Xiaojian,Yao Xinsheng
Background Kang-Ai injection is widely used as an adjuvant therapy drug for many cancers, leukopenia, and chronic hepatitis B. Circulating alkaloids and saponins are believed to be responsible for therapeutic effects. However, their pharmacokinetics (PK) and excretion in vivo and the risk of drug–drug interactions (DDI) through inhibiting human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes remain unclear.Methods PK and excretion of circulating compounds were investigated in rats using a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC–MS) method. Further, the inhibitory effects of nine major compounds against eleven CYP and UGT isozymes were assayed using well-accepted specific substrate for each enzyme.Results After dosing, 9 alkaloids were found with Cmax and t1/2 values of 0.17–422.70 μmol/L and 1.78–4.33 h, respectively. Additionally, 28 saponins exhibited considerable systemic exposure with t1/2 values of 0.63–7.22 h, whereas other trace saponins could be negligible or undetected. Besides, over 90% of alkaloids were excreted through hepatobiliary and renal excretion. Likewise, astragalosides and protopanaxatriol (PPT) type ginsenosides also involved in hepatobiliary and/or renal excretion. Protopanaxadiol (PPD) type ginsenosides were mainly excreted to urine. Furthermore, PPD-type ginsenosides were extensively bound (fu-plasma approximately 1%), whereas astragalosides and PPT-type ginsenosides displayed fu-plasma values of 12.35% and 60.23–87.36%, respectively. Moreover, matrine, oxymatrine, astragaloside IV, ginsenoside Rg1, ginsenoside Re, ginsenoside Rd, ginsenoside Rc, and ginsenoside Rb1 exhibited no inhibition or weak inhibition against several common CYP and UGT enzymes IC50 values between 8.81 and 92.21 μM. Through kinetic modeling, their inhibition mechanisms towards those CYP and UGT isozymes were explored with obtained Ki values. In vitro-in vivo extrapolation showed the inhibition of systemic clearance for CYP or UGT substrates seemed impossible due to [I]/Ki no more than 0.1.Conclusion sWe summarized the PK behaviors, excretion characteristics and protein binding rates of circulating alkaloids, astragalosides and ginsenosides after intravenous Kang-Ai injection. Furthermore, weak inhibition or no inhibition towards these CYP and UGT activities could not trigger harmful DDI when Kang-Ai injection is co-administered with clinical drugs primarily cleared by these CYP or UGT isozymes.
研究领域:
药理学
·
药剂学
·
药物代谢
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Naikuan Fu,Ao Li,Jing Zhang,Peng Zhang,Hong Zhang,Shicheng Yang,Jianhua Zhang
Due to their low osmolality and high tolerability , the highly water-soluble nonionic iodinated contrast agents, such as Ioversol (IV), are widely used as clinical agents for CT imaging. However, their clinical applications still are severely limited by the rapid renal excretion , serious adverse effects especially contrast-induced nephropathy and inefficient targetability. Various nanocarriers have demonstrated tremendous potential for achieving high imaging efficiency and low side effects. However, few nanoparticulate contrast agents can simultaneously integrate the desirable functions for imaging, including high loading capacity of iodine, high structure stability for systemic circulation , high biocompatibility and high radiopacity. Herein, we designed and prepared a kind of new radiopaque liposome-camouflaged iodinated mesoporous silica nanoparticles (OIV-MSNs@Liposomes) as contrast agents in CT imaging. Their composition, structure, morphology, biocompatibility and physicochemical properties as well as in vitro radiopacity were investigated in detail. The results indicated that OIV-MSNs@Liposomes can integrate their individual advantages of liposomes and MSNs, thus exhibiting great potential for use in the CT imaging. Considering the simple preparation process and readily available starting materials as well as enhanced biosafety and high performance in X-ray attenuation, the strategy reported here offers a versatile route to efficiently deliver highly water-soluble nonionic iodinated contrast agents for enhanced CT imaging, which are unattainable by traditional means.
研究领域:
纳米技术
·
医学成像
·
药物科学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）