高坤,孙进,何仲贵
GAO Kun,SUN Jin,HE Zhong-gui(School of Pharmacy

• 1:沈阳药科大学药学系
• 2:沈阳药科大学药学系
• 3:沈阳药科大学药学系 辽宁沈阳100016
• 4:辽宁沈阳100016

摘要(Abstract)：

目的综述药物的生物药剂学性质对药物口服吸收的影响。方法依据本课题组在该领域的工作,查阅国内外30篇相关文献,并结合最新进展进行归纳总结。结果药物的溶解性、稳定性、膜通透性和首过作用等生物药剂学性质是影响药物口服后经胃肠道吸收的主要因素。结论药物的生物药剂学性质显著影响口服药物的吸收,在药物结构设计、制剂处方设计、临床合理用药及口服给药系统开发中应重视评价药物的生物药剂学性质。
Objective To review the impacts of biopharmaceutical characteristics on oral drug absorption.Methods Based on our previous work and related published papers,the effects of biopharmaceutical characteristics of drugs on their absorption were discussed.Results The solubility,stability in gastrointestinal tract,membrane permeability and presystemic metabolism of drugs were the major factors on oral drug absorption.Conclusions Biopharmaceutical characteristics of drugs have vital influences on oral drug absorption.In view of drug molecular structure and formulation designs,rational use of clinical drugs and oral drug-delivery systems designs,the biopharmaceutical properties of the drug should be regarded as an indispensable component.

关键词(KeyWords)： 生物药剂学性质;口服药物;溶解性;稳定性;膜通透性;首过作用
biopharmaceutical characteristics;oral drug;solubility;stability;membrane permeability;first-pass effect(presystemic metabolism)

Abstract:

Keywords:

基金项目(Foundation): 国家863课题(No.2004AA2Z3100);; 辽宁省教育厅资助项目(No.2004F118)

作者(Author): 高坤,孙进,何仲贵
GAO Kun,SUN Jin,HE Zhong-gui(School of Pharmacy

参考文献(References)：

• [1]CALDWELL GW.Compound optimization in early-and late-phase drug discovery:Acceptable pharmacoki-netic properties utilizing combined physicochemical,invitro and in vivo screens[J].Current Opinion in DrugDiscovery&Development,2000,3(1):30-41.
• [2]SUN Jin,SHI Jie-ming,ZHANG Tian-hong,et al.Im-pact of release characteristics of sinomenine hydrochlo-ride dosage forms on its pharmacokinetics in beagledogs[J].World Journal of Gastroenterology,2005,11(29):4547-4551.
• [3]魏树辉,何仲贵,王立云,等.盐酸青藤碱口服渗透泵控释片的制备及其释药影响因素考察[J].沈阳药科大学学报,2003,20(3):165-169.
• [4]冯波,何仲贵,赵临襄,等.沙丁胺醇包合物缓释片的制备及其体外释放研究[J].沈阳药科大学学报,2002,19(1):18-22.
• [5]冯波,何仲贵,赵临襄,等.沙丁胺醇包合物缓释片在家犬体内药动学研究[J].中国医药工业杂志,2002,33(10):491-493.
• [6]何仲贵,唐星,刘峰,等.盐酸地尔硫卓缓释片的制备及体外释放度[J].沈阳药科大学学报,2000,17(5):313-315.
• [7]HE Zhong-gui,ZHANG Tian-hong,TANG Xing,etal.Preparation and pharmacokinetic characterization ofsustained release melatonin tablet[J].Journal of Chi-nese Pharmaceutical Sciences,2003,12(2):82-86.
• [8]CUI Sheng-miao,ZHAO Chun-shun,TANG Xing,etal.Study on the bioavailability of puerarin from puer-aria lobata isoflavone self-microemulsifying drug de-livery systems and tablets in rabbits by liquid chro-matography-mass spectrometry[J].Biomedical Chro-matography,2005,19(5):375-378.
• [9]SUN Jin,ZHANG Tian-hong,QIU Feng,et al.Impactof pharmaceutical dosage forms on the pharmacokinet-ics of roxithromycin in healthy human volunteers[J].JAntimicrob Chemother,2005,55(5):796-799.
• [10]CAHN LM,LOWES S,HIRST BH.The ABCs ofdrug transport in intestine and liver:efflux proteinslimiting drug absorption and bioavailability[J].Euro-pean Journal of Pharmaceutical Sciences,2004,21(1):25-51.
• [11]AVDEEF A,BOX KJ,COMER JE,et al.pH-metriclogP 10 determination of liposomal membrane-waterpartition coefficients of ionizable drugs[J].PharmRes,1998,15(2):209-215.
• [12]孙进,王思玲,程刚,等.磷脂膜色谱及其在生物药剂学中的应用[J].药学学报,2003,38(6):475-480.
• [13]高坤,孙进,何仲贵.肠道转运蛋白在药物吸收中的重要作用[J].药学学报,2006,41(2):97-102.
• [14]TAMAII,NAKANISHI T,HAYASHI K,et al.Thepredominant contribution of oligopeptide transporterPepT1 to intestinal absorption of beta-lactam antibi-otics in the rat small intestine[J].J Pharm Pharmacol,1997,49(8):796-801.
• [15]MIZUMA T,OHTA K,HAYASHI M,et al.Intestinalactive absorption of sugar-conjugated compounds byglucose transport system:implication of improvementof poorly absorbable drugs[J].Biochem Pharmacol,1992,43(9):2037-2039.
• [16]BARRAND MA,BAGRIJ T,NEO SY.Multidrug re-sistance-associated protein:a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion[J].Gen Pharmaco,1997,28(5):639-645.
• [17]SUN Jin,CHENG Gang,HE Zhong-gui,et al.Mul-tidrug resistance P-glycoprotein:crucial significance indrug disposition and interaction[J].Med Sci Monit,2004,10(1):RA5-14.
• [18]YANG S,GURSOY RN,LAMBERT G,et al.En-hanced oral absorption of paclitaxel in a novel self-mi-cromulsifying drug delivery system with or withoutconcomitant use of-Pglycoprotein inhibitors[J].Pharm Res,2004,21(2):261-270.
• [19]LO Yu-li,HUANG Jin-ding.Effect of sodium deoxy-cholate and sodium caprate on the transport of epiru-bicin in human intestinal epithelial Caco-2 cell layersand everted gut sacs of rats[J].Biochemical Pharma-cology,2000,59:665-672.
• [20]DINTAMAN JM,SILVERMAN JA.Inhibition ofP-glycoprotein byD--tαocopheryl polyethylene glycol1000 succinate(TPGS)[J].Pharma Res,1999,16(10):1550-1556.
• [21]PRUEKSARITANONT T,DELUNA P,GORHAM LM,et al.In vitroandin vivoevaluations of intestinalbarriers of the zwitterion L-767679 and its carboxylester prodrug L-775318[J].Drug Metab Dispos,1998,26(6):520-527.
• [22]WATKINS PB.The barrier function of CYP3A4 andP-glycoprotein in the small bowel[J].Adv Drug DelivRev,1997,27(2-3):161-170.
• [23]孙进,孙勇兵,何仲贵.转运蛋白在药物肝胆转运中的重要作用[J].药学学报,2005,40(8):460-465.
• [24]TAMAI I,NEZU J,UCHINO H,et al.Molecular i-dentification and characterization of novel members ofthe human organic anion transporter(OATP)family[J].Biochem Biophys Res Commun,2000,273(1):251-260.
• [25]KRAMER W,WESS G,SCHUBERT G,et al.Liverspecific drug targeting by coupling to bile acids[J].JBiol Chem,1992,267(26):18598-18604.
• [26]YAMAZAKI M,AKIYAMA S,NITNUMA K,et al.Biliary excretion of pravastafin in rats:contribution ofthe excretion pathway mediated by canalicular mulfis-pecific organic anion transporter[J].Drug Metab Dis-pos,1997,25(10):1123-1129.
• [27]SEELIG A.A general pattern for substrate recognitionby-Pglycoprotein[J].Eur J Biochem,1998,251(1-2):252-261.
• [28]THOMPSON IL,Jansen PLM.Genetic defects in hep-atocanalicular transport[J].Semin Liver Dis,2000,20(3):365-372.
• [29]SMIT JW,SCHINKEL AH,WEERT B,et al.Hepa-tobiliary and intestinal clearance of amphiphilic cationicdrugs in mice in which both mdr1a and mdr1b geneshave been disrupted[J].Br J Pharmacol,1998,124(2):416-424.
• [30]NARITOMI Y,TERASHITA S,KIMURA S,et al.Prediction of human hepatic clearance from in vivo an-imal experiments and in vitro metablolic studies withliver microsomes from animals and humans[J].DrugMetab Dispos,2001,29(10):1316-1324.