朱亮藥學(xué)導(dǎo)論3藥動(dòng)學(xué)-zhuliang

1、藥物代謝動(dòng)力學(xué) Pharmacokinetics,朱亮上海交通大學(xué)醫(yī)學(xué)院,Why do me need to know PK? ---- Optimize drug therapy to obtain a predictable response!,(1) Drug of choice(2) How much (3) How often (4) For how long,Definition,體內(nèi)藥物濃度隨時(shí)間變化的動(dòng)

2、力學(xué)規(guī)律,,PK discusses how a drug is: absorbed (taken into the body) distributed (moved into various tissues) metabolized (changed into form that can be excreted) excreted (removed from the body),,Drug Administration,,Dr

3、ug Concentration in Systemic Circulation,,Drug in Tissues of Distribution,,Drug Metabolism or Excreted,Drug Concentration at Site of Action,Pharmacologic Effect,Clinical Response,Toxicity,Efficacy,,,,,,,,,,,,,,,,,Absorpt

4、ion,Distribution,,Elimination,,Pharmacokinetics,Pharmacodynamics,Drug must have necessary properties to be transported from its site of administration to its site of action.Drug should be inactivated or excreted from t

5、he body at a reasonable rate so its actions will be of appropriate duration.,Example: Penetration of Antimicrobial Agents into Anatomic Compartments,Levofloxacin achieves skin tissue/plasma peak concentration ratio of

6、1.4, epithelial lining fluid to plasma ratio of 2.8, and urine to plasma ratios of 67. The failure rate of therapy was 0% in patients with urinary tract infections, 3% in patients with pulmonary infections, and 16% in pa

7、tients with skin and soft tissue infections,To be effective, each antibiotic has to get to where the pathogen is, to penetrate into the infected compartment,,penicillin G, are actively transported out of the cerebrospina

8、l fluid (CSF) and achieve CSF concentrations of only 0.5-5% of that achieved in plasma,,,,,Drug at action site,Metabolites,Excreted drug,Drug in body,,,用藥后藥物在體內(nèi)量的變化曲線,% of dose,,第 一 節(jié) 藥物分子的跨膜轉(zhuǎn)運(yùn),Drug Transport,一、藥物通過細(xì)胞膜的方

9、式：,水溶性小分子藥物通過細(xì)胞膜的水通道受流體靜壓或滲透壓的影響腸粘膜上皮細(xì)胞及其它大多數(shù)細(xì)胞膜孔道4～8Å, 僅水、尿素等小分子水溶性物質(zhì)能通過, 分子量>100者即不能通過腎小球毛細(xì)血管內(nèi)皮孔道約40Å，除蛋白質(zhì)外，血漿中的溶質(zhì)均能通過,濾過(Filtration)—水溶性擴(kuò)散,絕大多數(shù)藥物采用此方式 擴(kuò)散速度與脂溶性正相關(guān) 藥物還需同時(shí)具有水溶性 受藥物理化性質(zhì)和pH影響 分子量小 脂溶性

10、高 非解離型 極性小的 容易透過 存在離子障(ion trapping)現(xiàn)象,簡(jiǎn)單擴(kuò)散—脂溶性擴(kuò)散,,The non-ionized molecules usually are more lipid soluble and can diffuse readily across the cell membrane. In contrast, the ionized molecules usually are less able

11、to penetrate the lipid membrane because of their low lipid solubility, and passage will depend on the leakiness of the membrane related to the membrane's electrical resistance.,Ka =,[ H+ ] [ A? ][HA],,pKa = pH - log

12、,[ A? ][HA],,[ A? ][HA],,10 pH-pKa =,酸性藥 ：,堿性藥：,pH和pKa決定藥物分子解離多少,,,,Henderson–Hasselbalch equation,,,,A? + H+?HA,HA?H+ + A?,[ A? ][HA],,10pH-pKa =,pH=7,pH=4,1,1,102,105,色甘酸鈉 (Cromolyn Sodium)：pKa = 2,= 107-2 = 105,

13、[ A? ][HA],,10pH-pKa =,= 104-2 = 102,,,弱酸性藥物在酸性的環(huán)境中解離少,容易透過細(xì)胞膜在堿性的環(huán)境中解離多,不容易透過細(xì)胞膜弱堿性藥物在酸性的環(huán)境中解離多,不容易透過細(xì)胞膜在堿性的環(huán)境中解離少,容易透過細(xì)胞膜,主動(dòng)轉(zhuǎn)運(yùn) (Active transport),逆濃度梯度，耗能需要載體載體對(duì)藥物有選擇性飽和性 競(jìng)爭(zhēng)性,易化擴(kuò)散 (Facilitated diffusion;

14、 Carrier-mediated diffusion)如：Glucose, Iron, 5-fluorouracil, calcium, lead 需特異性載體順濃度梯度，不耗能,膜動(dòng)轉(zhuǎn)運(yùn)（cytosis/pinocytosis）,胞飲（pinocytosis）藥物通過膜內(nèi)陷小泡進(jìn)入細(xì)胞胞吐（exocytosis）藥物通過胞裂外排由細(xì)胞內(nèi)轉(zhuǎn)運(yùn)至細(xì)胞外This mechanism is important for the

15、 transport of some macromolecules (e.g. insulin, which crosses the blood-brain barrier by this process), but not for small molecules.,二 藥物在體內(nèi)的存在形式,游離型（free）結(jié)合型（bound）Transmembrane movement of drug generally is limit

16、ed to unbound drug; thus drug-protein complexes constitute an inactive reservoir of drug that can influence both therapeutic as well as unwanted drug effects.,第 二 節(jié) 藥物的體內(nèi)過程 Absorption, Distribution, Metabolism and Excr

17、etion,吸收,藥物由給藥部位進(jìn)入全身血循環(huán)的過程存在于除靜脈給藥方式外的所有其它給藥途徑途徑：oral, sub-lingual, injection, inhalation, rectal, intra-vaginal, intra-nasal. topical ?吸收快慢次序：血管內(nèi)>吸入>舌下>直腸>肌肉內(nèi)>皮下>口服>皮膚,口服,The oral route (PO) is

18、usually preferred.AdvantagesThe safest, most convenient, and most economicalDisadvantages Limited absorption of some drugsIrritation to the GI mucosaDestruction of some drugs by digestive enzymes or low gastric pH

19、Irregularities in absorption or propulsion in the presence of food or other drugsThe need for cooperation on the part of the patientFirst pass elimination.First pass metabolism of a drug can be avoided by sublingual a

20、dministration and partially avoided by rectal administration.,小腸吸收,消化道吸收最主要部位吸收面積大血流量豐富，毛細(xì)血管壁通透性強(qiáng)藥物與之接觸時(shí)間長(zhǎng)小腸既存在弱酸性環(huán)境，也存在弱堿性環(huán)境,胃腸道各部位吸收面積(m2) 口腔 0.5-l .0直腸 0.02胃 0.1-0.2小腸 100大腸 0.04-0.07,pH of Selective

21、Body Fluids,血液循環(huán)示意圖,首過消除(Presystemic/First-pass eliminaiton)藥物由用藥部位到達(dá)全身血循環(huán)前被組織器官代謝損失掉一部分的現(xiàn)象,,First passmetabolism of drugs may occur as they cross the intestine or transit the livereg: nitroglycerinOther drugs may be

22、 destroyed before absorptioneg: penicillinSuch reactions decrease delivery to the target tissues,靜脈注射給藥（Intravenous） 直接將藥物注入血管不存在“吸收”過程，無“首關(guān)消除”肌肉注射和皮下注射 (Intramuscular and subcutaneous injection)被動(dòng)擴(kuò)散＋過濾，吸收快而全 毛

23、細(xì)血管壁孔半徑40Å，大多水溶性藥可濾過,注射給藥特點(diǎn),The administration of injection are technically more difficult and usually must be performed by a heath care professional.A. advantages include:(1) a faster onset(2) more reliable abso

24、rption(3) no first pass metabolismB. Disadvantages include:(1) more difficult administration.(2) pain or necrosis at the site of injection(3) possibility of infection(4) toxicity from a bolus intravenous injection

25、(5) necessity of dissolving the drug if given intravenously.,呼吸道給藥,通過噴霧或氣霧給藥方式大顆粒粘附于呼吸道粘膜發(fā)揮局部作用小分子由呼吸道粘膜或肺泡上皮細(xì)胞吸收氣體和揮發(fā)性藥物直接進(jìn)入肺泡，吸收迅速 肺泡表面積大（100-200m2） 血流量大（肺毛細(xì)血管面積80m2 ）,舌下、直腸給藥局部給藥經(jīng)皮給藥：通過皮膚吸收產(chǎn)生局部或全身作用，藥物吸收緩慢，作用持

26、久經(jīng)粘膜吸收快于皮膚口腔、鼻、支氣管、直腸、陰道皮下緩釋給藥,影響藥物吸收的因素,藥物理化性質(zhì)和劑型首過消除給藥途徑甘露醇 ivgtt, po硫酸鎂 ivgtt, po藥物/食物相互作用Environmental pHBlood flow to the absorption siteTotal surface area available for absorptionContact time at the ab

27、sorption surfaceExpression of P-glycoprotein,藥物吸收定量參數(shù),達(dá)峰時(shí)間（Tmax）達(dá)峰濃度（Cmax）曲線下面積（AUC）生物利用度（F）,2. 分布 （Distributation),藥物從血循環(huán)到達(dá)全身各個(gè)組織的過程規(guī)律：先“分布”，然后“再分布”分布部位存在選擇性在血液循環(huán)和器官組織中濃度可達(dá)動(dòng)態(tài)平衡前者間接反映靶器官藥物濃度后者決定藥物效應(yīng)和毒性強(qiáng)弱血藥濃度預(yù)測(cè)

28、療效強(qiáng)弱,,脂溶性 組織器官血流量 組織結(jié)合、分布的選擇性 血漿蛋白結(jié)合率 體液pH和藥物離解度 體內(nèi)屏障,Factors modulating drug distribution:,血漿蛋白結(jié)合(Plasma protein binding),可逆性（Reversible equilibrium）可飽和性（Saturable）DP（Non-permeable）不能透過細(xì)胞膜，不能產(chǎn)生藥效 非特異性和競(jìng)爭(zhēng)性 (Nons

29、pecific & competitive）,對(duì)血漿蛋白質(zhì)結(jié)合有相互作用的藥物,思考,血漿蛋白結(jié)合率高的藥物藥量增加超過蛋白結(jié)合能力后，再增加藥量，則.....?血漿蛋白結(jié)合率高的藥物聯(lián)合應(yīng)用時(shí),.....?血漿蛋白含量降低或變質(zhì)后,......?,,絕大多數(shù)藥物采用此方式 擴(kuò)散速度與脂溶性正相關(guān) 藥物還需同時(shí)具有水溶性 受藥物理化性質(zhì)和pH影響 分子量小 脂溶性高 非解離型 極性小的 容易透過 存在離子

30、障(ion trapping)現(xiàn)象,簡(jiǎn)單擴(kuò)散—脂溶性擴(kuò)散,,,,A? + H+?HA,HA?H+ + A?,[ A? ][HA],,10pH-pKa =,pH=7,pH=4,1,1,102,105,色甘酸鈉 (Cromolyn Sodium)：pKa-2, 酸性,= 107-2 = 105,[ A? ][HA],,10pH-pKa =,= 104-2 = 102,,,總量100001,總量101,弱酸性藥物在酸性的環(huán)境中解

31、離少,容易透過細(xì)胞膜在堿性的環(huán)境中解離多,不容易透過細(xì)胞膜弱堿性藥物在酸性的環(huán)境中解離多,不容易透過細(xì)胞膜在堿性的環(huán)境中解離少,容易透過細(xì)胞膜,弱酸性藥物苯巴比妥中毒,用碳酸氫鈉解救的理論依據(jù)？,問題：,,血腦屏障 (Blood-brain barrier, BBB),由毛細(xì)血管壁和N膠質(zhì)細(xì)胞構(gòu)成,,大分子、脂溶度低的藥物難透過有中樞作用的藥物脂溶度高 也有載體轉(zhuǎn)運(yùn)，如葡萄糖可通過 可變：炎癥時(shí)，通透性↑，大劑量青霉素有

32、效,血腦屏障 (Blood-brain barrier, BBB),Plasma and cerebrospinal fluid concentrations of thienamycin following an intravenous dose (25 mg/kg) in normal or meningitis rabbits,55,代謝（生物轉(zhuǎn)化, Metabolism, Biotransformation）：,Animals

33、 have evolved complex systems that detoxify foreign chemicals ('xenobiotics')部位：主要在肝臟，其它如胃腸、肺、皮膚、腎步驟：分兩步反應(yīng)，Phase I and phase IIBoth phases decrease lipid solubility, thus increasing renal elimination,56,,The

34、 kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules.Therefore, lipid-soluble agents must first be metabolized into more polar (hydr

35、ophilic) substances in the liver using two general sets of reactions, called Phase I and Phase II,I期反應(yīng)（Phase I）：氧化、還原、水解、引入或脫去基團(tuán)(-OH、-CH3、-NH2、-SH),II期反應(yīng)（Phase II）：內(nèi)源性葡萄糖醛酸、硫酸、醋酸等與藥物或I期反應(yīng)的代謝物結(jié)合生成極性很高的代謝產(chǎn)物,,Phase I reac

36、tions convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2. Phase I metabolism may increase, decrease, or leave unaltered the drug’s pharmacolog

37、ic activity.Reversal of order of the phases: Not all drugs undergo Phase I and II reactions in that order. For example, isoniazid is first acetylated (a Phase II reaction) and then hydrolyzed to isonicotinic acid (a Pha

38、se I reaction).,60,,,,61,,The two phases of drug metabolism,I期反應(yīng)（Phase I）,are catabolic（氧化、還原、水解、引入或脫去基團(tuán)(-OH、-CH3、-NH2、-SH)）the products are often more chemically/pharmacologically reactive and hence, paradoxically, som

39、etimes more toxic or carcinogenic than the parent drugoften involve a monooxygenase system in which cytochrome P450 plays a key role,62,The cytochrome P450 monooxygenase system,the enzymes are haem proteinsthe reduced

40、forms combine with carbon monoxide to form a pink compound with absorption peaks near 450 nm 選擇性低變異性、個(gè)體差異大可被誘導(dǎo)或抑制,63,Examples of drugs that are substrates of P450 isoenzymes,64,,Phase 2 reactions also normally termina

41、te the biological activity of the drug, although for drugs like morphine and minoxidil, glucuronide and sulfate conjugates, respectively, are more pharmacologically active than the parentSince the rate of conjugation is

42、 faster and the process leads to an increase in hydrophilicity of the drug, phase 2 reactions are generally considered to assure the efficient elimination and detoxification of most drugs,Human CYP Enzymes Important in L

43、iverMetabolism of Drugs a,,質(zhì)子泵抑制劑(PPIs)的代謝,,,CYP3A,CYP2C19,PPIs,無活性代謝物,CYP2C19活性狀況決定PPI血藥濃度,我國(guó)漢族CYP2C19基因型分組的構(gòu)成比,藥酶誘導(dǎo) (Induction)：苯巴比妥、利福平，環(huán)境污染物等自身耐受性 (引起耐藥) 交叉耐受性 (同一藥物代謝酶的底物),藥酶抑制 (Inhibition)：西米替丁、普羅地芬等競(jìng)爭(zhēng)代謝途

44、徑而導(dǎo)致藥物代謝酶被抑制。,無誘導(dǎo),苯巴比妥誘導(dǎo),苯并芘誘導(dǎo),氯苯唑胺(骨松藥)濃度（µg/g組織）,時(shí)間（小時(shí)）,大鼠，注射誘導(dǎo)劑2次/日?4日,藥物代謝酶的活性可被誘導(dǎo)或抑制,,問題奧美拉唑和氯吡格雷的作用機(jī)制各是什么？奧美拉唑?yàn)楹螘?huì)影響氯吡格雷的療效？臨床上為何特別關(guān)注藥物間的相互作用？,4. 排泄 (Excretion),腎臟消化道 肺 皮膚 唾液 乳汁等,特點(diǎn)：多屬被動(dòng)轉(zhuǎn)運(yùn)，少數(shù)屬于主動(dòng)轉(zhuǎn)運(yùn)排泄或

45、分泌器官中，藥物濃度較高時(shí)既有治療價(jià)值，又可能產(chǎn)生不良反應(yīng)排泄器官功能變化對(duì)藥物作用有影響,,,,,,,酸性 堿性,,99%的H20和脂溶性藥物,尿 1ml/min,腎小球?yàn)V過率 (GFR) 125ml/min,,,,,,血漿流量 650ml/min,濾過 主動(dòng)分泌 重吸收,藥物及代謝物腎臟排泄方式,腎小球?yàn)V過血液中絕大部分游離藥物可被濾過腎小管主動(dòng)分泌遵循主動(dòng)運(yùn)輸規(guī)律：競(jìng)爭(zhēng)、飽和..

46、..腎小管被動(dòng)重吸收符合被動(dòng)轉(zhuǎn)運(yùn)規(guī)律：脂溶性、解離度小...改變尿液pH值影響重吸收,由腎小管主動(dòng)分泌排泄的藥物,尿液pH值對(duì)藥物排泄的影響,Liver,,Gut,Feces excretion,Portal vein,膽汁排泄 (biliary excretion) 和肝腸循環(huán),(Enterohepatic recycling),Bile duct,,① 治療膽道感染② 有肝腸循環(huán)的藥物作用明顯延長(zhǎng)中止肝腸循環(huán),促進(jìn)藥

47、物排出,可解毒(如強(qiáng)心苷)。,意義:,藥物體內(nèi)各過程的相互聯(lián)系,體內(nèi)藥物的藥量-時(shí)間關(guān)系 Time course of drug concentration,一、一次給藥,血漿藥物濃度 (mg/L),藥物濃度-時(shí)間曲線,常用血漿藥物濃度-時(shí)間曲線藥物及其代謝物體內(nèi)過程之媒介藥物作用靶組織、靶器官、各種體液和組織中藥物濃度與血中藥物濃度保持一定的比例關(guān)系采集樣本較其他方便,,,,hrs,Plasma concentration,二

48、、多次給藥 (Constant repeated administration of drugs)（1）穩(wěn)態(tài)血藥濃度 (Steady-state concentration) 目的：多次給藥使血藥濃度達(dá)有效范圍,Examples of drugs where therapeutic drug monitoring (TDM) of plasma concentrations is used,85,藥物在體

49、內(nèi)積蓄和從體內(nèi)消除時(shí)程,87.5% 94% 97%,,,,藥物消除動(dòng)力學(xué) Elimination Kinetics,體內(nèi)藥物濃度因不斷消除而隨時(shí)間不斷變化,一級(jí)消除動(dòng)力學(xué) (First order elimination kinetics ) n = 1 dC/dt = - kC,零級(jí)消除動(dòng)力學(xué) (Zero order elimination kinetics) n = 0

50、 dC/dt = k,dC/dt = - kCn,k：消除速率常數(shù)(Rate constant for elimination),,,一、一級(jí)消除動(dòng)力學(xué) 轉(zhuǎn)運(yùn)（消除）速度與濃度差成正比,t,二、零級(jí)消除動(dòng)力學(xué)Ct=-k0t+C0 t1/2=0.5C0/k0,血漿藥物濃度消除一半所需時(shí)間,一、消除半衰期（Half-life, T1/2）,零級(jí)消除動(dòng)力學(xué): t1/2 = 0.5 ? C0/k,一級(jí)消除動(dòng)力學(xué): t

51、1/2 =0.693/Ke,,,t1/2,t1/2,t1/2,t1/2,,t1/2,,,Slope(斜率) = -Ke/2.303,時(shí)間（h）,時(shí)間（h）,血漿藥物濃度,血漿藥物濃度,,單位時(shí)間消除藥量與濃度成正比半衰期不隨濃度而變,單位時(shí)間消除藥量不變半衰期隨濃度而變,,,一級(jí)與零級(jí)消除比較,藥物代謝動(dòng)力學(xué)重要參數(shù) Important Parameters in Pharmacokinetics,峰濃度 Cmax，達(dá)峰時(shí)間 T

52、max,血管外給藥后藥物在血漿中的最高濃度值和出現(xiàn)時(shí)間，分別代表藥物吸收的程度和速度,曲線下面積 AUC,時(shí)量曲線和橫坐標(biāo)圍成的區(qū)域，表示一段時(shí)間內(nèi)藥物在血漿中的相對(duì)累積量,h,mg/ml,消除速率常數(shù)（k or ke）,表示單位時(shí)間內(nèi)機(jī)體能消除藥物的固定分?jǐn)?shù)或百分比，單位為時(shí)間的倒數(shù)。如某藥的k＝0.2h-1，表示機(jī)體每小時(shí)可消除該小時(shí)起點(diǎn)時(shí)體內(nèi)藥量的20％一級(jí)消除動(dòng)力學(xué)時(shí)，k為一常數(shù)。是衡量藥物消除快慢的一臨床常用參數(shù)計(jì)算：k

53、＝0.693/t1/2,消除半衰期（Half-life, T1/2）,血漿藥物濃度消除一半所需時(shí)間 一級(jí)消除動(dòng)力學(xué)T1/2 = 0.693/k與濃度無關(guān)，為恒定值,反映藥物消除快慢固定劑量、固定時(shí)間給藥經(jīng)5個(gè)t1/2血藥濃度達(dá)到穩(wěn)態(tài)一次用藥后經(jīng)5個(gè)t1/2體內(nèi)藥量消除97%決定給藥間隔時(shí)間肝腎功能 t1/2,,,意 義,零級(jí)消除動(dòng)力學(xué)藥物達(dá)一定濃度，機(jī)體消除能力達(dá)最大后的消除動(dòng)力學(xué)。 給藥劑量越大，半衰期越長(zhǎng)

54、 T1/2 = 0.5 ? C0/k,,清除率 (Clearance)來自生理學(xué)肌酐清除率的概念 單位時(shí)間內(nèi)多少容積血漿中的藥物被清除，反映肝腎功能 單位：L/h或ml/min CL=CL腎臟＋CL肝臟＋CL其它 計(jì)算公式： CL = D/AUC,表觀分布容積 (Apparent Volume of distribution),體內(nèi)藥物總量與血漿藥物濃度之比

55、 Vd＝D／C0Vd非體內(nèi)生理空間,,血漿3L 細(xì)胞間液11L 細(xì)胞內(nèi)液32L,70kg體重， 全身總體液量：46L,了解藥物在體內(nèi)分布 5L,分布于血漿 10～20L分布于細(xì)胞外液 40L分布全身體液 100L則集中分布于某一器官,意義： 推測(cè)藥物在體內(nèi)的分布范圍 Digoxin：0.5mg 0.78 ng/ml Vd = 645 L 主要

56、分布于肌肉（包括心肌，其濃度為血濃30倍）和脂肪組織 計(jì)算用藥劑量： C =D/Vd,,? 相對(duì)生物利用度：不同制劑AUC比較 F = (AUC受試制劑 ? AUC標(biāo)準(zhǔn)制劑) × 100%,生物利用度(Bioavailability) 藥物到達(dá)全身血循環(huán)內(nèi)的相對(duì)量,絕對(duì)生物利用度：,特點(diǎn)及意義: 1). 受制劑(晶型、賦形劑、生產(chǎn)工藝等) 、膜通透性、首過效應(yīng)等影響。 2).影響血藥濃

57、度，從而影響藥效和毒性。 3).是評(píng)價(jià)制劑優(yōu)劣的主要參數(shù)之一。,Bioequivalence,Regulatory authorities-which have to make decisions about the licensing of products that are 'generic equivalents' of patented products-require evidence of '

58、bioequivalence' based on Cmax and Tmax as well as AUC(0-∞). For most drugs, each of these parameters must lie between 80% and 125% of the lead product for the new generic product to be accepted as bioequivalent.,Var

59、iation in oral absorption among different formulations of digoxin,三個(gè)藥廠生產(chǎn)的地高辛,實(shí)例：某新藥大鼠經(jīng)靜脈和皮下注射后藥動(dòng)學(xué)參數(shù),,Bioequivalence:Two related drug preparations are bioequivalent if they show comparable bioavailability and similar tim