Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present stud...Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.展开更多
Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy,while the mechanism was not very clear.Here,the authors ...Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy,while the mechanism was not very clear.Here,the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3,the liver transporters OATP1 B1 and OATP1 B3,and the intestine transporter OATP2 B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation(YHP)comprising Corydalis yanhusuo(CYH)and Angelica dahurica(AD),which could relieve pain by restraining the central system.The results show that tetrahydropalmatine(TDE),the major component of CYH,could be transported by OAT3 into kidney,OATP1 B1 and OATP1 B3 into liver,while imperatorin(IPT)and isoimperatorin(ISP),the two key components of AD,and AD extract showed strong inhibition to OAT1 and OAT3.What’s more,AD extract also exerted strongly inhibition to human transporters OATP1 B1 and OATP1 B3.It was also detected that IPT,ISP,and AD extract significantly downregulated the expression of Oatplal,Oafp1 a4,and Oatp1 b2 of liver in mice.The in vivo results show that the concentration of TDE in liver and kidney significantly decreased,while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT,ISP,and AD extract.These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney.That is to say,TDE with bitter taste could"flood up"into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD.This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3,OATP1 B1,and OATP1 B3,but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD.This study may offer a valuable clue to illustrate the mechanism of展开更多
The disposition of most drugs is highly dependent on specialized transporters. OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells, identified as contr...The disposition of most drugs is highly dependent on specialized transporters. OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells, identified as contributors to xenobiotic and endogenous organic anion secretion. It is well known that cholestasis may cause renal damage. Impairment of kidney function produces modifications in the renal elimination of drugs. Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis. Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters. The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.展开更多
Stellera chamaejasme L.is a traditional Chinese medicine with a long history to treat stubborn skin ulcer,and it also has antiviral and antitumor effects.Neochamaejasmine B(NCB),Neochamaejasmine A(NCA)and Chamaechromo...Stellera chamaejasme L.is a traditional Chinese medicine with a long history to treat stubborn skin ulcer,and it also has antiviral and antitumor effects.Neochamaejasmine B(NCB),Neochamaejasmine A(NCA)and Chamaechromone(CMC)are the major components in dried roots of Stellera chamaejasme L..Our studies suggested that NCB,NCA and CMC are inhibitors of Organic anion transporter 1(OAT1).OAT1 is encoded by solute carrier family 22 member 6 gene(SLC22 A6)in humans and plays a critical role in the organic anion drug uptake and excretion in the kidney.Lamivudine is the typical substrate of OAT1 and is frequently used in combination with other antiviral drugs in clinical antiviral treatments.The aim of this study is to investigate the interaction and its mechanism between these bi-flavone components in Stellera chamaejasme L.and lamivudine via OAT1 both in vitro and in vivo.In vitro,the uptake studies in Madin-Darby canine kidney(MDCK)cells overexpressing OAT1 suggested that NCB inhibited the uptake of 6-CFL and lamivudine.Similar results were obtained for NCA and CMC.NCB was a noncompetitive and competitive inhibitor interaction with OAT1.IC50 values of NCB,NCA and CMC for inhibiting OAT1-mediated lamivudine transport were 2.46,8.35 and 0.61μmol·L^–1,respectively.In vivo,the pharmacokinetic results of lamivudine in rats showed that the mean area under the plasma concentration-time curve(AUC0-∞)and maximal plasma concentration(Cmax)of lamivudine after co-administration is increased 2.94-fold and 1.87-fold,respectively,compared to lamivudine administration alone.The results of interactions between lamivudine and these bi-flavone components in Stellera chamaejasme L.extracts via OAT1 in vivo are consistent with studies in vitro.The inhibition of OAT1-mediated uptake of lamivudine by NCB,NCA and CMC is the possible mechanism for Stellera chamaejasme L.extracts improving the oral bioavailability of lamivudine in rats.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81025025,81001671,and J1103512)Natural Science Foundation of Jiangsu Province(No.BK2010365)~~
基金supported by a grant from the National Natural Science Foundation of China,China(Nos.81874324,81473280,and U1608283)Dalian Science and technology innovation found,China(No.2018J12SN065)
文摘Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.
基金supported by the National Natural Science Foundation of China(grant Nos.81430096 and 81503154)Tianjin Science and Technology Support Key Projects(grant No.17YFZCSY01170,China)Research Unit for Drug Metabolism,Chinese Academy of Medical Sciences(grant No.2019RU009,China)
文摘Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy,while the mechanism was not very clear.Here,the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3,the liver transporters OATP1 B1 and OATP1 B3,and the intestine transporter OATP2 B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation(YHP)comprising Corydalis yanhusuo(CYH)and Angelica dahurica(AD),which could relieve pain by restraining the central system.The results show that tetrahydropalmatine(TDE),the major component of CYH,could be transported by OAT3 into kidney,OATP1 B1 and OATP1 B3 into liver,while imperatorin(IPT)and isoimperatorin(ISP),the two key components of AD,and AD extract showed strong inhibition to OAT1 and OAT3.What’s more,AD extract also exerted strongly inhibition to human transporters OATP1 B1 and OATP1 B3.It was also detected that IPT,ISP,and AD extract significantly downregulated the expression of Oatplal,Oafp1 a4,and Oatp1 b2 of liver in mice.The in vivo results show that the concentration of TDE in liver and kidney significantly decreased,while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT,ISP,and AD extract.These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney.That is to say,TDE with bitter taste could"flood up"into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD.This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3,OATP1 B1,and OATP1 B3,but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD.This study may offer a valuable clue to illustrate the mechanism of
基金Supported by Grants from FONCyT (PICT 05-20201) and CONICET (PIP 5592)
文摘The disposition of most drugs is highly dependent on specialized transporters. OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells, identified as contributors to xenobiotic and endogenous organic anion secretion. It is well known that cholestasis may cause renal damage. Impairment of kidney function produces modifications in the renal elimination of drugs. Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis. Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters. The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.
基金supported by the National Key R&D Program of China(Nos.2017YFE0102200,2017YFC0908600)Zhejiang Provincial Natural Science Foundation of China(LY15H310004,LY16H280014)Natural Science Foundation of China(No.81573502)
文摘Stellera chamaejasme L.is a traditional Chinese medicine with a long history to treat stubborn skin ulcer,and it also has antiviral and antitumor effects.Neochamaejasmine B(NCB),Neochamaejasmine A(NCA)and Chamaechromone(CMC)are the major components in dried roots of Stellera chamaejasme L..Our studies suggested that NCB,NCA and CMC are inhibitors of Organic anion transporter 1(OAT1).OAT1 is encoded by solute carrier family 22 member 6 gene(SLC22 A6)in humans and plays a critical role in the organic anion drug uptake and excretion in the kidney.Lamivudine is the typical substrate of OAT1 and is frequently used in combination with other antiviral drugs in clinical antiviral treatments.The aim of this study is to investigate the interaction and its mechanism between these bi-flavone components in Stellera chamaejasme L.and lamivudine via OAT1 both in vitro and in vivo.In vitro,the uptake studies in Madin-Darby canine kidney(MDCK)cells overexpressing OAT1 suggested that NCB inhibited the uptake of 6-CFL and lamivudine.Similar results were obtained for NCA and CMC.NCB was a noncompetitive and competitive inhibitor interaction with OAT1.IC50 values of NCB,NCA and CMC for inhibiting OAT1-mediated lamivudine transport were 2.46,8.35 and 0.61μmol·L^–1,respectively.In vivo,the pharmacokinetic results of lamivudine in rats showed that the mean area under the plasma concentration-time curve(AUC0-∞)and maximal plasma concentration(Cmax)of lamivudine after co-administration is increased 2.94-fold and 1.87-fold,respectively,compared to lamivudine administration alone.The results of interactions between lamivudine and these bi-flavone components in Stellera chamaejasme L.extracts via OAT1 in vivo are consistent with studies in vitro.The inhibition of OAT1-mediated uptake of lamivudine by NCB,NCA and CMC is the possible mechanism for Stellera chamaejasme L.extracts improving the oral bioavailability of lamivudine in rats.
