蛋白多肽类药物的药代动力学研究进展

　　,(中国药科大学药代中心,南京210009)　　[]　综述了蛋白多肽类药物药代动力学机制研究的某些进展。蛋白多肽类药物的稳定性和渗透性及给药途径的不同是影响药物吸收的主要因素;其分布则取决于药物的理化性质、自身受体的分布、蛋白结合率及组织器官的特性;体内广泛存在的蛋白多肽酶在蛋白多肽类药物的降解中起主导作用;而受体介导清除可能是该类药物从体内清除的主要机制。[]　蛋白多肽类药物;药代动力学;机制[]R969.1;R977.6　　[]A　　[]1003-3734(2001)12-0884-04AdvancesinpharmacokineticresearchofproteinpolypeptidesZHANGQi,WANGGuang-ji(CenterforPharmacokinetics,ChinaPharmaceuticalUniversity,Nanjing210009,China)[Abstract]　Thepharmacokineticresearchofproteinpolypeptideswasreviewedinthispaper.Fromreviewofdocumentsitcanbeconcludedthatthestability,permeability,androuteofadministra-tionofproteinpolypeptidesarethemainfactorstoinfluencetheiradsorption;thephysicalandchemicalproperties,distributionofself-receptors,proteinbindingrateandspecialityoftissueandorgansarethefactorstodeterminetheirdistribution;theenzymesofproteinpolypeptidesarethefactorstodeterminetheirmetabolism;andreceptormediatedeliminationsystemmaybetheireliminationmechanism.[Keywords]　proteinpolypeptides;pharmacokinetics;mechanism　　,,、、、,[1]。,,。,。1　、。,;,3:①/。②。③。。,(internaliza-tion)。,(cell-penetratingpeptide),[2]。1.1　　2。。,pH。pH、、、、。,、[3]。,、;β-、、。-(Brush-bordermembrane,BBM)。,。1000,,—884—　ChineseJournalofNewDrugs2001,Vol.10No.1220011012　。1.2　　、。,:(im)=(sc)=(ip),。,、。1.2.1　(ParenteralRoute)　、。,,。,,,、。1.2.2　(OralRoute)　2。,:B12[4];;;();-。1.2.3　(NasalRoute)　,。,(Pseudo-first-passeffect)。,P450,3～4NADPH-P450。、,,、[5]。1.2.4　(TransdermalRoute)　:,,,。。,,。、。1.2.5　　[6]、。、、、[7]。,(site-specificdrugdeliverysys-tems),。、、[8]。2　,,。:、、、、,。、。,0.04～0.2L·kg-1,1～20L·kg-1。,,、。,,。,、。,。,[9]。,、[10]。(masking),;;,。、,。—885—　ChineseJournalofNewDrugs2001,Vol.10No.1220011012　(CNS),、-(BBB),,。BBB:;BBB;CNS[11]。、、CNS[12]。。。[125I]-rhuIGF(insulin-likegrowthfactor)168～204mL·min-1·kg-1;,15.5～48mL·min-1·kg-1,,0.5～10mL·min-1·kg-1。[125I]-rhuIGF[4]。3　,。,,。3.1　　,、[13]。、、。,P4503A4(CYP3A4),P-(P-gp)CYP3A4[14]。3.2　　8。,125I-TGF-β(Transforminggrowthfac-torβ),83%。。,。,、,。3.3　　,、、[15]。;,,,,。3.4　　。,。Ⅳ(DAPⅣ)、(PPCE)。,。9,、P450。P450。4　。3×104,、-2。,。,,,。,,。[16]。,,40min,,。,,,,,。,(TPA)。。,,,,,()。。、。5　—886—　ChineseJournalofNewDrugs2001,Vol.10No.1220011012　,。(Thyrotropin-releas-inghormone,TRH)20.67h,3,40。。,,,。,,,,,。6　,。,,。[]　张琪(1972-),女,研究方向:蛋白多肽类药物药代动力学。联系电话[phone],E-mail:[e-mail]。[][1]　.[J].,1997,6(1)∶13-18.[2]　LindgrenM,HallbrinkM,ProchiantzA,etal.Cell-penetratingpeptides[J].TrendsPharmacolSci,2000,21(3)∶99-103.[3]　YangCY,DantzigAH,PidgeonC.Intestinalpeptidetransportsystemsandoraldrugavailability[J].PharmRes,1999,16(9)∶1331-1343.[4]　Russell-JonesGJ.UseofvitaminB12conjugatestodeliverproteindrugsbytheoralroute[J].CritRevTherDrugCarrierSyst,1998,15(6)∶557-586.[5]　SarkarMA.Drugmetabolisminthenasalmucosa[J].PharmRes,1992,9(1)∶1-3.[6]　YuJ,CheinYW.Pulmonarydrugdelivery:physiologicandmechanis-ticaspects[J].CritRevTherDrugCarrierSyst,1997,14(4)∶395-453.[7]　SayaniAP,ChienYW.Systemicdeliveryofpeptidesandproteinsacrossabsorptivemucosa[J].CritRevTherDrugCarrierSyst,1996,13(1-2)∶85-184.[8]　PettitDK,GombotzWR.Thedevelopmentofsite-specificdrugdeliverysystemsforproteinandpeptidebiopharmaceuticals[J].TrendsBiotechnol,1998,16(8)∶343-349.[9]　BellD,McDermottBJ.Calcitoningenerelatedpeptideinthecar-diovascularsystem:characterizationofreceptorpopulationsandtheir(patho)hysiologicalsignificance[J].PharmacolRev,1996,48(2)∶253-288.[10]　HokfeltT,BrobergerC,XuZQ,etal.Neuropeptides———anoverview[J].Neuropharmacology,2000,39(8)∶1337-1356.[11]　BegleyDJ.Theblood-brainbarrier:principlesfortargetingpep-tidesanddrugstothecentralnervoussystem[J].JPharmPhar-macol,1996,48(2)∶136-146.[12]　HallerMF,SaltzmanWM.Localizeddeliveryofproteinsinthebrain:cantransportbecustomized[J].PharmRes,1998,15(3)∶377-385.[13]　MariottiF,HuneauJF,MaheS,etal.Proteinmetabolismandthegut[J].CurrOpinClinNutrMetabCare,2000,3(1)∶45-50.[14]　WacherVJ,SilvermanJA,ZhangY,etal.RoleofP-glycoproteinandcytochromeP4503Ainlimitingoralabsorptionofpeptidesandpeptidomimetics[J].JPharmSci,1998,87(11)∶1322-1330.[15]　GaribottoG,TessariP,SaccoP,etal.Aminoacidmetabolism,substrateavailabilityandthecontrolofproteindynamicsinthehumankidney[J].JNephrol,1999,12(4)∶203-211.[16]　BehrTM,GoldenbergDM,BeckerW.Reducingtherenaluptakeofradiolabeledantibodyfragmentsandpeptidesfordiagnosisandtherapy:presentstatus,futureprospectsandlimitations[J].EurJNuclMed,1998,25(2)∶201-212.(收稿日期:2001-07-19)　　　《》(〔2001〕476),::①;②;③;④;⑤;⑥。:①;②;③;④;⑤;⑥;⑦。、、、,,,。国家药品监督管理局市场监督司—887—　ChineseJournalofNewDrugs2001,Vol.10No.1220011012