Objective: to explore the mechanism of transportation and transformation of dampness by the way of the expression of organic anion transporting polypeptide (oatp) superfamily member 2a1 (oatp2a1) mRNA in rat with sple...Objective: to explore the mechanism of transportation and transformation of dampness by the way of the expression of organic anion transporting polypeptide (oatp) superfamily member 2a1 (oatp2a1) mRNA in rat with spleen deficiency syndrome and the significance in transportation and transformation of dampness. Methods: 32 wistar male rats were divided randomly into four groups: normal group (n = 6), normal + AA group (n = 6), spleen deficiency group (n = 10), Spleen deficiency + AA group (n = 10). After reserpine-induced spleen deficiency model was made, intragastric administration of aristolochic acid (AA) was adopted for three days, the expression of oatp2a1 mRNA were detected in the tissues of lung, liver, kidney, stomach, small intestine and large intestine in four groups by using Fluorescent Quantitative-Polymerase Chain Reaction (FQ-PCR). Results: the expression of oatp2a1 mRNA in above six tissues could be detected. The ex-pression of oatp2a1 mRNA in liver tissue of rat with spleen deficiency syndrome was up-regulated compared to normal group (P = 0.035, P < 0.05), the expression of oatp2a1 mRNA in small intestinal tissue of rat with spleen deficiency syndrome was down-regulated compared to normal group (P = 0.004, P < 0.01), the expression of oatp2a1 in intestinal tissue in normal + AA group is down-regulated compared to normal group (P = 0.032, P < 0.05). Conclusions: oatp2a1 might be one of the material basis involved in transportation and transformation of dampness. The changes of expression of oatp2a1 mRNA in small intestine, liver tissue suggests that small intestine, liver might play an important role in the transportation and transformation of dampness in the state of spleen deficiency. We further concluded that the function of spleen’s governing transportation and transformation of dampness was not only including the function of the gastrointestinal, but also part of the liver function in some degree, which needs to be further studied.展开更多
Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided i...Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided into three groups: blank control group, model group and Cangfudaotan Tang group, 12 cases in each one. After PCOS rat models were made, rats of Cangfudaotan Tang group were treated with Cangfudaotan Tang (1.42 g/kg/d) by intragastric administration for 14 days;blank control and model group were given with isodose saline. The expression of oatp2b1 mRNA/Protein in liver and kidney tissues was measured and the level of testosterone (T), follicle stimulating hormone(FSH), estradiol (E<sub>2</sub>), luteinizing hormone(LH), Serum total cholesterol (TG), Triacylglycerols (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were detected at the same time. Results: Compared with blank control group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL, LH, FSH, T in model group were significantly increased (P < 0. 05), while the level of HDL was significantly decreased (P < 0. 05);compared with model group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL in Cangfudaotan Tang group were significantly lowered (P < 0.05);the level of HDL was significantly higher;the oatp2b1 protein in kidney and liver tissues had different degrees of expression, while there was no statistical significance among the three groups. Conclusions: Oatp2b1 might be one of the material bases participating in transportation and transformation of phlegmy dampness. The mechanism of Cangfudaotan Tang treating phlegm dampness type of PCOS may be achieved by regulating the expression of oatp2b1.展开更多
Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the v...Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokineticpharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.展开更多
Drug-drug interaction(DDI)is one of causes of adverse drug events and can result in lifethreatening consequences.Organic anion-transporting polypeptide(OATP)2B1 is a major uptake transporter in the intestine and contr...Drug-drug interaction(DDI)is one of causes of adverse drug events and can result in lifethreatening consequences.Organic anion-transporting polypeptide(OATP)2B1 is a major uptake transporter in the intestine and contributes to transport various clinically used therapeutic agents.The intestine has a high risk of DDI,because it has a special propensity to be exposed to a high concentration of drugs.Thus,understanding drug interaction mediated by OATP2B1 in the absorption process is important for the prevention of adverse drug events,including decrease in the therapeutic effect of co-administered drugs.Acute drug interaction occurs through the direct inhibitory effect on transporters,including OATP2B1.Moreover,some compounds such as clinically used drugs and food components have an acute stimulatory effect on transport of co-administered drugs by OATP2B1.This review summarizes the acute stimulatory effect on the transport mediated by OATP2B1 and discusses the mechanisms of the acute stimulatory effects of compounds.There are two types of acute stimulatory effects,substrate-independent and-dependent interactions on OATP2B1 function.The facilitating translocation of OATP2B1 to the plasma membrane is one of causes for the substrate-independent acute stimulatory effect.On the contrary,the substrate-dependent effect is based on the direct binding to the substrate-binding site or allosteric progesterone-binding site of OATP2B1.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 compatibility theory.展开更多
Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encod...Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.展开更多
文摘Objective: to explore the mechanism of transportation and transformation of dampness by the way of the expression of organic anion transporting polypeptide (oatp) superfamily member 2a1 (oatp2a1) mRNA in rat with spleen deficiency syndrome and the significance in transportation and transformation of dampness. Methods: 32 wistar male rats were divided randomly into four groups: normal group (n = 6), normal + AA group (n = 6), spleen deficiency group (n = 10), Spleen deficiency + AA group (n = 10). After reserpine-induced spleen deficiency model was made, intragastric administration of aristolochic acid (AA) was adopted for three days, the expression of oatp2a1 mRNA were detected in the tissues of lung, liver, kidney, stomach, small intestine and large intestine in four groups by using Fluorescent Quantitative-Polymerase Chain Reaction (FQ-PCR). Results: the expression of oatp2a1 mRNA in above six tissues could be detected. The ex-pression of oatp2a1 mRNA in liver tissue of rat with spleen deficiency syndrome was up-regulated compared to normal group (P = 0.035, P < 0.05), the expression of oatp2a1 mRNA in small intestinal tissue of rat with spleen deficiency syndrome was down-regulated compared to normal group (P = 0.004, P < 0.01), the expression of oatp2a1 in intestinal tissue in normal + AA group is down-regulated compared to normal group (P = 0.032, P < 0.05). Conclusions: oatp2a1 might be one of the material basis involved in transportation and transformation of dampness. The changes of expression of oatp2a1 mRNA in small intestine, liver tissue suggests that small intestine, liver might play an important role in the transportation and transformation of dampness in the state of spleen deficiency. We further concluded that the function of spleen’s governing transportation and transformation of dampness was not only including the function of the gastrointestinal, but also part of the liver function in some degree, which needs to be further studied.
文摘Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided into three groups: blank control group, model group and Cangfudaotan Tang group, 12 cases in each one. After PCOS rat models were made, rats of Cangfudaotan Tang group were treated with Cangfudaotan Tang (1.42 g/kg/d) by intragastric administration for 14 days;blank control and model group were given with isodose saline. The expression of oatp2b1 mRNA/Protein in liver and kidney tissues was measured and the level of testosterone (T), follicle stimulating hormone(FSH), estradiol (E<sub>2</sub>), luteinizing hormone(LH), Serum total cholesterol (TG), Triacylglycerols (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were detected at the same time. Results: Compared with blank control group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL, LH, FSH, T in model group were significantly increased (P < 0. 05), while the level of HDL was significantly decreased (P < 0. 05);compared with model group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL in Cangfudaotan Tang group were significantly lowered (P < 0.05);the level of HDL was significantly higher;the oatp2b1 protein in kidney and liver tissues had different degrees of expression, while there was no statistical significance among the three groups. Conclusions: Oatp2b1 might be one of the material bases participating in transportation and transformation of phlegmy dampness. The mechanism of Cangfudaotan Tang treating phlegm dampness type of PCOS may be achieved by regulating the expression of oatp2b1.
文摘Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokineticpharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.
基金This review was in part supported by the Japan Society for the Promotion of Science(JSPS)Kakenhi grant number 19K21219.
文摘Drug-drug interaction(DDI)is one of causes of adverse drug events and can result in lifethreatening consequences.Organic anion-transporting polypeptide(OATP)2B1 is a major uptake transporter in the intestine and contributes to transport various clinically used therapeutic agents.The intestine has a high risk of DDI,because it has a special propensity to be exposed to a high concentration of drugs.Thus,understanding drug interaction mediated by OATP2B1 in the absorption process is important for the prevention of adverse drug events,including decrease in the therapeutic effect of co-administered drugs.Acute drug interaction occurs through the direct inhibitory effect on transporters,including OATP2B1.Moreover,some compounds such as clinically used drugs and food components have an acute stimulatory effect on transport of co-administered drugs by OATP2B1.This review summarizes the acute stimulatory effect on the transport mediated by OATP2B1 and discusses the mechanisms of the acute stimulatory effects of compounds.There are two types of acute stimulatory effects,substrate-independent and-dependent interactions on OATP2B1 function.The facilitating translocation of OATP2B1 to the plasma membrane is one of causes for the substrate-independent acute stimulatory effect.On the contrary,the substrate-dependent effect is based on the direct binding to the substrate-binding site or allosteric progesterone-binding site of OATP2B1.
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 compatibility theory.
基金supported in whole or part by grants from the National Natural Science Foundation of China(No.81773808)the Science and Technology Commission of Shanghai Municipality(Nos.17140901000,17140901001 and 18430760400)supported from ECNU Multifunctional Platform for Innovation(011,China)
文摘Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.
