The human body consists of several physiological barriers that express a number of membrane transporters. For an orally absorbed drug the intestinal, hepatic, renal and blood-brain barriers are of the greatest importa...The human body consists of several physiological barriers that express a number of membrane transporters. For an orally absorbed drug the intestinal, hepatic, renal and blood-brain barriers are of the greatest importance. The ATP-binding cassette(ABC) transporters that mediate cellular efflux and the solute carrier transporters that mostly mediate cellular uptake are the two superfamilies responsible for membrane transport of vast majority of drugs and drug metabolites. The total number of human transporters in the two superfamilies exceeds 400, and about 40-50 transporters have been characterized for drug transport. The latest Food and Drug Administration guidance focuses on P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide 1B1(OATP1B1), OATP1B3, organic cation transporter 2(OCT2), and organic anion transporters 1(OAT1) and OAT3. The European Medicines Agency's shortlist additionally contains the bile salt export pump, OCT1, and the multidrug and toxin extrusion transporters, multidrug and toxin ex-trusion protein 1(MATE1) and MATE2/MATE2 K. A variety of transporter assays are available to test drugtransporter interactions, transporter-mediated drugdrug interactions, and transporter-mediated toxicity. The drug binding site of ABC transporters is accessible from the cytoplasm or the inner leaflet of the plasma membrane. Therefore, vesicular transport assays utilizing inside-out vesicles are commonly used assays, where the directionality of transport results in drugs being transported into the vesicle. Monolayer assays utilizing polarized cells expressing efflux transporters are the test systems suggested by regulatory agencies. However, in some monolayers, uptake transporters must be coexpressed with efflux transporters to assure detectable transport of low passive permeability drugs. For uptake transporters mediating cellular drug uptake, utilization of stable transfectants have been suggested. In vivo animal models complete the testing battery. Some issues, such as in vivo relevance, gender difference, age and ontogeny issues can only be addressed using in vivo models. Transporter specificity is provided by using knock-out or mutant models. Alternatively, chemical knock-outs can be employed. Compensatory changes are less likely when using chemical knockouts. On the other hand, specific inhibitors for some uptake transporters are not available, limiting the options to genetic knock-outs.展开更多
The matured,ripen,and dried seeds of Scaphium affine(Mast.) Pierre,known as Pangdahai(PDH) in Chinese and recorded as Sterculia lychnophora Hance(scientific synonym) in the 2015 edition of the Chinese Pharmacopeia,hav...The matured,ripen,and dried seeds of Scaphium affine(Mast.) Pierre,known as Pangdahai(PDH) in Chinese and recorded as Sterculia lychnophora Hance(scientific synonym) in the 2015 edition of the Chinese Pharmacopeia,have been widely used in traditional Chinese medicine,Japanese folk medicine,Vietnamese traditional medicine,traditional Thai medicine and Indian traditional medicine.The decoctions of the seeds are used as a remedy for pharyngitis,laryngitis,constipation,cough,menorrhagia,and pain management.This review is aimed at fully collating and presenting a systematic and comprehensive overview of the ethnopharmacological uses of PDH,its phytochemical constituents,pharmacological activities,and toxicological profile.Additionally,this review aims to reveal the therapeutic potentials as well as the important scientific gaps in the research of this traditional medicine that need to be filled so as to provide a comprehensive data for its development,utilization and application.From our extensive review of literatures,the teas(water decoctions) of PDH,which largely contain very polar constituents like polysaccharides,are used in the treatment of constipation,pharyngitis,and pain traditionally and ethno-medicinally and their use have been justified by pharmacological studies carried out on the polysaccharides and aqueous extracts.Additionally,this review has revealed that the organic(ethanolic and methanolic) extracts of PDH possess diverse pharmacological(anti-inflammatory,anti-ulcer,anti-pyretic,anti-microbial,anti-obesity and analgesic) effects,yet have received little attention.Most studies on PDH have been focused on the polysaccharides(large molecular weight metabolites),resulting in a major scientific gap in our knowledge on PDH.Furthermore,this review has also shown that few studies have been done in the areas of quality control,pharmacokinetics,and toxicological studies of PDH.展开更多
基金Supported by FP7 IMI MIP-DILI:Mechanism-based integrated systems for the prediction of drug-induced liver injuryFP7 Eustroke,Health-F2-2008-202213:European Stroke Research Network+1 种基金TUDAS-1-2006-0029,OMFB-00505/2007:Development of HTS kit for analyzing transporter-drug interactions using cholesterol treated insect-cells expressing human MXR transporterGOP-1.1.1-11-2011-0017:Integrated preclinical tools for the determination and the enhancement of drug absorption
文摘The human body consists of several physiological barriers that express a number of membrane transporters. For an orally absorbed drug the intestinal, hepatic, renal and blood-brain barriers are of the greatest importance. The ATP-binding cassette(ABC) transporters that mediate cellular efflux and the solute carrier transporters that mostly mediate cellular uptake are the two superfamilies responsible for membrane transport of vast majority of drugs and drug metabolites. The total number of human transporters in the two superfamilies exceeds 400, and about 40-50 transporters have been characterized for drug transport. The latest Food and Drug Administration guidance focuses on P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide 1B1(OATP1B1), OATP1B3, organic cation transporter 2(OCT2), and organic anion transporters 1(OAT1) and OAT3. The European Medicines Agency's shortlist additionally contains the bile salt export pump, OCT1, and the multidrug and toxin extrusion transporters, multidrug and toxin ex-trusion protein 1(MATE1) and MATE2/MATE2 K. A variety of transporter assays are available to test drugtransporter interactions, transporter-mediated drugdrug interactions, and transporter-mediated toxicity. The drug binding site of ABC transporters is accessible from the cytoplasm or the inner leaflet of the plasma membrane. Therefore, vesicular transport assays utilizing inside-out vesicles are commonly used assays, where the directionality of transport results in drugs being transported into the vesicle. Monolayer assays utilizing polarized cells expressing efflux transporters are the test systems suggested by regulatory agencies. However, in some monolayers, uptake transporters must be coexpressed with efflux transporters to assure detectable transport of low passive permeability drugs. For uptake transporters mediating cellular drug uptake, utilization of stable transfectants have been suggested. In vivo animal models complete the testing battery. Some issues, such as in vivo relevance, gender difference, age and ontogeny issues can only be addressed using in vivo models. Transporter specificity is provided by using knock-out or mutant models. Alternatively, chemical knock-outs can be employed. Compensatory changes are less likely when using chemical knockouts. On the other hand, specific inhibitors for some uptake transporters are not available, limiting the options to genetic knock-outs.
基金supported by the National Standardization Project of Traditional Chinese Medicine(No.ZYBZH-C-JS-29)State Key Program of National Natural Science Foundation of China(No.81430095)
文摘The matured,ripen,and dried seeds of Scaphium affine(Mast.) Pierre,known as Pangdahai(PDH) in Chinese and recorded as Sterculia lychnophora Hance(scientific synonym) in the 2015 edition of the Chinese Pharmacopeia,have been widely used in traditional Chinese medicine,Japanese folk medicine,Vietnamese traditional medicine,traditional Thai medicine and Indian traditional medicine.The decoctions of the seeds are used as a remedy for pharyngitis,laryngitis,constipation,cough,menorrhagia,and pain management.This review is aimed at fully collating and presenting a systematic and comprehensive overview of the ethnopharmacological uses of PDH,its phytochemical constituents,pharmacological activities,and toxicological profile.Additionally,this review aims to reveal the therapeutic potentials as well as the important scientific gaps in the research of this traditional medicine that need to be filled so as to provide a comprehensive data for its development,utilization and application.From our extensive review of literatures,the teas(water decoctions) of PDH,which largely contain very polar constituents like polysaccharides,are used in the treatment of constipation,pharyngitis,and pain traditionally and ethno-medicinally and their use have been justified by pharmacological studies carried out on the polysaccharides and aqueous extracts.Additionally,this review has revealed that the organic(ethanolic and methanolic) extracts of PDH possess diverse pharmacological(anti-inflammatory,anti-ulcer,anti-pyretic,anti-microbial,anti-obesity and analgesic) effects,yet have received little attention.Most studies on PDH have been focused on the polysaccharides(large molecular weight metabolites),resulting in a major scientific gap in our knowledge on PDH.Furthermore,this review has also shown that few studies have been done in the areas of quality control,pharmacokinetics,and toxicological studies of PDH.
