一般临床药物代谢动力学回顾

GeneralClinicalPharmacokinetics

Review2UniversityofFloridaWorkingProfessionalDoctorofPharmacyProgramChristineCrain,Pharm.D.,BCPSClinicalQuestion?A60yearoldwomanistakingquinidinefortreatmentofatrialfibrillation.ShehasalsobeenprescribedfluconazolefortreatmentofaCandidaUTIandcisapridetocontrolsxofGERD.Wouldyouexpectanyofthesedrugstointeractbasedonthehepaticenzymesbywhichtheyaremetabolized?

AnswertoClinicalQuestionHepaticEnzyme(s)AffectedQuinidine Inhibits2D6 Metabolizedby3A4Fluconazole Potentialinhibitor of3A4Cisapride Metabolizedby3A4DrugEliminationLiver-PrimarilyMetabolismKidney-PrimarilyExcretionHepaticClearanceTheefficiencyoftheliverinremovingdrugfromthebloodstreamisreferredtoastheextractionratio(E).Withhighextractiondrugs,Eiscloserto1Withlowextractiondrugs,Eiscloserto0HepaticClearanceCLH=QHFpCLiQH+FpCLiQH=HepaticbloodflowFp=FractionoffreedruginplasmaCLi=IntrinsicclearanceHepaticClearanceCLH=QHFpCLiQH+FpCLiDrugswithahighintrinsicclearance=QHFpCLiFpCLiCLH=QHHepaticClearanceCLH=QHFpCLiQH+FpCLi=QHFpCLiQHCLH=FpCLiDrugswithalowintrinsicclearanceIntrinsicClearanceHigh

CLiLow

CLipropranolol warfarinlidocaine phenytoinmorphine theophyllinenitroglycerin diazepamClinicalQuestion?Smokingisknowntoincreasetheenzymesresponsiblefortheophyllinemetabolism.Wouldapatientwithahistoryofsmokinglikelyrequireahigher,lower,orequivalenttheophyllinetotaldailydosecomparedtoanonsmoker?ClinicalQuestion?Apatientinthecoronarycareunitisstartedonlidocainefortreatmentofventriculararrhythmias.Ifthispatienthasseverecongestiveheartfailure(EF<20%),howwouldtherequireddailydosageoflidocainelikelybeaffected?AnswertoClinicalQuestionCLH=QHFpCLiQH+FpCLiCLH=QHCHFDecreasesQHHalf-LifeThetimefortheconcentrationofdrugintheplasmatodecreasebyone-halfconc(logscale)1051**Time(hours)123SteadyStateConcTimeCavg,ssCmax,ssCmin,ssSteadyStateDurationofDrugAdministration(Half-Lives)SteadyStateConcentrationReached1 502 753 87.54 93.755 96.8756 98.47357 99.25ClinicalQuestion?Apatientisadmittedtothehospitalwithcarbamazepinetoxicity.Aninitialserumconcentrationis24mcg/ml.Assumingahalf-lifeofapproximately18hours,howlongwillittakeforthispatienttoreachaserumlevelof6mcg/ml?AnswertoClinicalQuestion24mcg/ml12mcg/ml6mcg/ml18hours18hours36hrsClinicalQuestion?Apatientisstartedondiltiazemforthetreatmentofhypertension.(InitialaverageBP=160/98)Adosageregimenofdiltiazem60mgpotidisinitiated.Approx.howlongwillittakeforthispatienttoreachsteadystate?AnswertoClinicalQuestionHalf-lifeofdiltiazem=6hoursSteadystateshouldbeachievedinapproximately5half-lives.Therefore,thispatientshouldreachsteadystateinapproximately30hours.ClinicalQuestion?A65yearoldmanisstartedondigoxin0.125mgpoqdforthetreatmentofcongestiveheartfailure.Ifaloadingdoseisnotgiven,approxi-matelyhowlongwillittakeforthispatienttoreachasteadystatedigoxinlevel?Ans璃wer辜to抄Cl局ini缠cal册Qu怠est熟ionThe认half纺-lif闭eof震dig抽oxin做is咬appr南ox.40h泛oursStea寺dys唉tate锦sho还uld立bea芳chie党ved晓byappr户oxim鹅atel柄y5蚕half顷-liv仆es.Ther慢efor间e,t驳his邀pati任ent眨shou搏lda阴chie弟veste冤ady漂st田ate剑di北gox呜in针lev均els母in光ap歇pro萌xi-mat对ely商8-挤9d柳ays秩.Eli第min筛ati华on祝Ra箭te肾Con愈sta冈nt年(ke)The幅frac焰tion水of现drug圆rem辆oved鹅peruni辽to喇ft红ime离(e穗.g.来ho百ur-1)Time层(ho骡urs)123456512.可3Drug矩Con共c.(lo护gs宗cal而e)**(Co,to)(C1,t1)lnC1=-ket+lnCoFir倘st-市Ord川er窗Eli取min秧ati野onTime应(ho秩urs)123456512.3Drug天Con湿c.(lo挎gs晶cal债e)**(Co,to)(C1,t1)slo森pe餐=-ke=夹lnC1-lnCot1-toElim些inat任ion东Rate凭Con贝stan想tTime啄(ho蜜urs)123456512.3Dru乱gC抢onc能.(log医sca率le)**(Co,to)(C1,t1)slop裁e=握-ke=服ln蒸5范-ln12.秆34hr-弓0程hrElim串inat认ion蜡Rate尺Con改stan孔tTim益e(娇hou狗rs)123456512.拜3Drug卖Con参c.(lo冻gs跳cal中e)**(Co,to)(C1,t1)slo声pe待=-ke=-0.米225hrCli肺nic酬al桑Que屋sti小on?A45谨yea双rol置dma雄nis念rec番eivi陆nggent强amic吗in1情60mg六IV店q12浸hr.Ap骨eak勉an芦dt愿rou年gh刷lev杂el蜻wer伐ed搬raw原nats桐tead掘yst耀ate.Peak弦= 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