一般臨床藥物代謝動(dòng)力學(xué)回顧

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纏cal冊(cè)Qu怠est熟ionThe認(rèn)half紡-lif閉eof震dig抽oxin做is咬appr南ox.40h泛oursStea寺dys唉tate錦sho還uld立bea芳chie黨ved曉byappr戶oxim鵝atel柄y5蠶half頃-liv仆es.Ther慢efor間e,t駁his邀pati任ent眨shou搏lda陰chie弟veste冤ady漂st田ate劍di北gox嗚in針lev均els母in光ap歇pro萌xi-mat對(duì)ely商8-擠9d柳ays秩.Eli第min篩ati華on祝Ra箭te腎Con愈sta岡nt年(ke)The幅frac焰tion水of現(xiàn)drug圓rem輛oved鵝peruni遼to喇ft紅ime離(e穗.g.來ho百ur-1)Time層(ho騾urs)123456512.可3Drug矩Con共c.(lo護(hù)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應(yīng)(ho秩urs)123456512.3Drug天Con濕c.(lo挎gs晶cal債e)**(Co,to)(C1,t1)slo森pe餐=-ke=夾lnC1-lnCot1-toElim些inat任ion東Rate憑Con貝stan想tTime啄(ho蜜urs)123456512.3Dru亂gC搶onc能.(log醫(yī)sca率le)**(Co,to)(C1,t1)slop裁e=握-ke=服ln蒸5范-ln12.稈34hr-弓0程hrElim串inat認(rèn)ion蠟Rate尺Con改stan孔tTim益e(嬌hou狗rs)123456512.拜3Drug賣Con參c.(lo凍gs跳cal中e)**(Co,to)(C1,t1)slo聲pe待=-ke=-0.米225hrCli肺nic酬al桑Que屋sti小on?A45謹(jǐn)yea雙rol置dma雄nis念rec番eivi陸nggent強(qiáng)amic嗎in1情60mg六IV店q12浸hr.Ap骨eak勉an蘆dt愿rou年gh刷lev雜el蜻wer伐ed搬raw原nats桐tead掘yst耀ate.Peak弦= 8.籃4mc猾g/ml解090恢0Tro劑ugh答=轎1.0腰mc府g/m申l 2付000Wha攪ti劇st囑his權(quán)pa延tie譯nt’撕se辜lim院ina所tio譜nrate息con膝stan化t(ke)a糧ndh蓄alf-幻玉life且?Fir擱st如Ord際er犁Eli陷min辯ati著onconctimekeslop暖e=鏟-ke=施lnC1-lnC0T1-T0**Ans蹤蝶wer薪to滴Cl燥ini腎cal蝦Qu屢est奇ion-ke=該lnC1-l民nC2t1-t2-ke=咐ln濤8.4愿-閣ln1.011hr=-0部.193籃5/hrRela婆tion江ship室Bet碗ween隨Dru涂gEl樸imin貴atio極nan您dHa梯lf-l泉ifeke=0.6炒93t1/2Answ陪ert并oCl儀inic探alQ隊(duì)uest究ionHal有f-l凝ife魔=疫0.6擋93keHalf旅-lif煌e=裙0.69庭30.1嶄935=3獵.58hrClin附ical暗Que穿stio絲式n?A65好yea偽rol濕dpa熟tien翼tis是adm蹦itte廢dtot束heh齒ospi殊tal叫with喂dig盜oxin顆tox差icit舍y.The倦di汁gox逐in萬ser涉um織con霞c.媽is集5n彎g/m檢l.How椅long脂sho狡uld古itt堆a(bǔ)ke習(xí)for夠the怎seru適mdigo獅xin穴conc海.to客dec鉛reas蝦eto寄1n鑼g/ml月?Fir溉st-正Ord訊er吹Equ攻ati告onCt=Coxe-ketAns否wer羽to壞Cl糾ini寶cal譜Qu巡壽est去ionThehal鏟f-l梳ifeof油dig盈oxi遺ni鎖sa尖ppr斃oxi永m(xù)at伏ely40沉hou討rs.ke矩=0.69聾3t1/2=叮0.0貝173賽/hrCt=Coxe-ket1摟=匪5xe-.址017解3tt=焰93h脆oursMain墊tena漁nce當(dāng)Dose滑Equ左atio瓣nko艷=Css尾xCLsMD=Css職xCLsCL=ke案xVdMD=Css但xkexVdRel東ati勢ons走h(yuǎn)ip袍Be候twe棄en絹Cle耐ara護(hù)nce昆,V唇da順nd撇Hal洽f-l茄ifeCL蘿=0.69嶼3t1/2VdLD淺vs食MD罰Equ坊ati怨onsLD=CpxVdMD=Css扭xke翅xVdCli授nic山al歌Que續(xù)sti乘on?A5旨0y鈔ear道ol拐dm汁an待is預(yù)to儀bestar但ted斗ona研mai肝nten及ance弦dos拒eofp殊roca周inam碎ide乞for暗the俘trea網(wǎng)tmen盜tofs起ever響ale弱piso尾des捧ofa建tria憂lfibr飯illa答tion芒.Ca煉lcul赤ate封aMD遮tha蜓twil葵lp隆rod猛uce胡an亞av消era貝ge呼ste井a(chǎn)dy漫st示atepro頌cai謎nam躲ide裳co銜nce惕ntr柜ati將ons叼ofappr罵oxim戲atel薦y6村mcg/更ml.何Assu絲式menlr種enal效fun堂ctio曾n.雅Wt:處68k膛gAns業(yè)wer廢to老Cl定ini牛cal恢Qu掃est寧ionMD=Css舊xke讓xVd=MD=Css律x俗0.逼693斥xVdt1/2=6mg/固L都x餡0.6卡934hrx2L/kg階x6積8kg朱=141mg/h方rx仰24h狼ours宗=3精400逃mgAns情wer常to厘Cl沉ini眉cal勾Qu信est錯(cuò)ionAssu童ming受app粥rox.扯85%妹abs惡orpt某ion,tot懼al挑dai帝ly銅dos吐e=訪40輪00軟mgGive斤as悄Proc外anS幣R10樂00m神gq6仆hORProc園anbi峰d20雜00mg隨po娛q12hRena網(wǎng)lEl倆imin蟻atio只nGlo椅mer丸ula仔rF月ilt災(zāi)rat摸ionTub筍ula侮rs唐ecr侵eti刮onTubu討lar釀reab沖sorp妖tionCre貓ati螺nin煎e(cuò)C護(hù)lea戰(zhàn)ran計(jì)ceCock仰crof乓t&解Gaul秀tEq郵uati冰onCLcr騙(ml嚇/mi揪n,們mal廊es)手=(14也0-age擦)(w朝eig煎ht)Crsx7莊2CLcr(惑ml/m綱in,溉fem)仍=(0.8姥5)(CLc普ri螞nm傷ale降s)Esti杯mate搬dEl陵imin樂atio倍nRa賭teC炭onst避ant揚(yáng)for斗Amin染ogly火cosi剖desGent浮amic絲式in,幫Tobr搞amyc置inke=仆0.0冷024煙(CrC餃l)+距.01Ami倚kac棉inke育=0蕉.00鄉(xiāng)豐279刑(C競rCl券)+丈.0啊1Van投com貧yci敢nke=浸0.0仇0083店(Cr稅Cl)微+.0濫044Cli端nic尸al訪Que民sti振on?A60帽yea遠(yuǎn)rol渴dwo激man甜int曬hei冊(cè)nten蜓sivecar掀eu訂nit井ha完sP濫seu涌dom些ona催sp炕neu論mon垃iaand呆iss舍t(yī)art里edo斃nce寄ftaz煮idim效ean梁dtobr額amyc禾in.脖The維phys判icia孤nas鴉ksy客out狐orec塔omm羊end喇a(chǎn)n章in誕iti勻al棚dos暈age榜re暗gim摟enfor攤tobr徑amyc薯in.寫Wt=賄52k狂gHt者=5語’4”SCr尼=呀1.4Wha求ti同nit浮ial訪re河gim胳en稍wou肝ld俊youreco樂mmen浩d?Ans疾wer餡to鄭Cl些ini扭cal虜Qu伐est竿ionIBW斷=45.趣5kg渴+(2丹.3x虧4i獲n.)福=54.飽7kgAct賓ual墨we情igh婆t=釣52概kgDos剖ing擠we堪igh辨t=凱52盟kgLD棋=CpxVdLD撈=1炎0m拔cg/帆ml決x0梅.3剝L/k復(fù)gx銳52扇kg址=156mg付(ro禍und竊to寸16聲0m邊g)Answ澇ert壺oCl分inic煎alQ燭uest編ionDesi絕red瞞Trou擋gh=受0.5題mcg斥/mlEst.匹ke師=0.縱0024中(Cr還Cl)魂+0.舌01Est論Cr睛Cl結(jié)=48鳥ml/源min棋(x少0.向85牢for趟fe簡mal唱e)蛙=4畜0.8便ml背/mn(Ple轟ase視use稍48m并l/mi建nas廟the經(jīng)CrC汽lfo遼rth梢isq沫uest柴ion榆sinc請(qǐng)eth繞eau廣thor姨neg百lect澆edt夸omu文ltip分lyb擾y0.侮85f兔orf薄emal驕ean唱dth賭eca末lcul邪atio距nsc罪onti笑nue批onu腰sing吵48走ml/m遼in.)Est比ke勤=越0.0融024臥(4罵8)證+0