EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2021
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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
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分子生物学
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临床医学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICAL AND ENVIRONMENTAL SCIENCES
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2019
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IF 1.917
Zhen Yong GUO,Wei Jie ZHAO,Mei Qin ZHENG,Shuo LIU,Chen Xia YAN,Peng LI,Shao Fa XU
Objective To assess the activities of biapenem against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. Methods Biapenem/clavulanate (BP/CL) was evaluated for in vitro activity against Mycobacterium tuberculosis ( Mtb ) multidrug-resistant (MDR) isolates, extensively drug-resistant (XDR) isolates, and the H37RV strain. BP/CL activity against the H37Rv strain was assessed in liquid cultures, in macrophages, and in mice. Results BP/CL exhibited activity against MDR and XDR Mtb isolates in liquid cultures. BP/CL treatment significantly reduced the number of colony forming units (CFU) of Mtb within macrophages compared with control untreated infected macrophages. Notably, BP/CL synergized in pairwise combinations with protionamide, aminosalicylate, and capreomycin to achieve a fractional inhibitory concentration for each pairing of 0.375 in vitro . In a mouse tuberculosis infection model, the efficacy of a cocktail of levofloxacin + pyrazinamide + protionamide + aminosalicylate against Mtb increased when the cocktail was combined with BP/CL, achieving efficacy similar to that of the positive control treatment (isoniazid + rifampin + pyrazinamide) after 2 months of treatment. Conclusion BP/CL may provide a new option to clinically treat MDR tuberculosis.
研究领域:
微生物学
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传染病学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2020
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IF 4.225
Liu Li-Wei,Shi Ying-Ying,Li Zhuo-Lun,Zuo Li-Hua,Tang Meng,Jing Zi-Wei,Zhao Hong-Yu,Xue Peng,Zhou Lin,Du Qiu-Zheng,Zhang Xiao-Jian,Sun Zhi
The drug combination of biapenem (BIPM) and xuebijing injection (XBJ) is commonly applied for the treatment of sepsis in China. However, the potential synergistic mechanism is still enigmatic. There have been no studies focused on the plasma metabolome alterations in sepsis after the intervention of this combination. In this work, an untargeted metabolomics approach was performed by liquid chromatography-mass spectrometry coupled with multivariate statistical analysis to provide new insights into the synergistic effect of BIPM in combination with XBJ. We characterized the metabolic phenotype of sepsis and described metabolic footprint changes in septic rats responding to XBJ and BIPM individually and in combination, in addition to histopathological and survival evaluation. A total of 91 potential biomarkers of sepsis were identified and 32 disturbed metabolic pathways were constructed. Among these biomarkers, 36 metabolites were reversely regulated by XBJ, mainly including glycerophospholipids, sphingolipids, free fatty acids (FFAs), bile acids and acylcarnitines; 42 metabolites were regulated by BIPM, mainly including amino acids, glycerophospholipids, and acylcarnitines; 72 metabolites were regulated after XBJ-BIPM combination treatment, including most of the 91 potential biomarkers. The results showed that the interaction between XBJ and BIPM indeed exhibited a synergistic effect by affecting some key endogenous metabolites, 15 metabolites of which could not be regulated when XBJ or BIPM was used alone. Compared with Model group, 13, 22, and 27 metabolic pathways were regulated by XBJ, BIPM, and XBJ-BIPM combination, respectively. It suggested that many more endogenous metabolites and metabolic pathways were significantly regulated after combination treatment compared with XBJ or BIPM monotherapy. Metabolisms of lipids, amino acids, acylcarnitines, and bile acids were common pathways involved in the synergistic action of XBJ and BIPM. This study was the first to employ metabolomics to elucidate the synergistic effect and decipher the underlying mechanisms of BIPM in combination with XBJ against sepsis. The results provide some support for clinical application of antibiotics in combination with traditional Chinese medicines and have important implications for the treatment of sepsis in clinic.
研究领域:
医学
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药理学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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