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1、药物代谢动力学 Pharmacokinetics,朱亮上海交通大学医学院,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,体内药物浓度随时间变化的动力学规律,PK discusses how a drug is:absorbed(taken into the body)distributed(moved into various tissues)
2、metabolized(changed into form that can be excreted)excreted(removed from the body),Drug Administration,Drug 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,
3、Absorption,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 the body at a reasonable rate so its actions will be of appropriate duration.,
4、Example:Penetration of Antimicrobial Agents into Anatomic Compartments,Levofloxacin achieves skin tissue/plasma peak concentration ratio of 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,
5、3%in patients with pulmonary infections,and 16%in patients 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 cerebrospinal fluid(CSF)and achieve CSF conc
6、entrations of only 0.5-5%of that achieved in plasma,Drug at action site,Metabolites,Excreted drug,Drug in body,用药后药物在体内量的变化曲线,%of dose,第 一 节 药物分子的跨膜转运,Drug Transport,一、药物通过细胞膜的方式：,水溶性小分子药物通过细胞膜的水通道受流体静压或渗透压的影响肠粘膜上皮细胞及其它大多数细胞膜孔道48,仅水、尿素等小分子水溶性物质能通过,分子量100者即不能通过肾小球毛细血管内皮孔道约40，除蛋白质外，血浆中的溶质均能通过,滤过(Filtr
7、ation)水溶性扩散,绝大多数药物采用此方式 扩散速度与脂溶性正相关 药物还需同时具有水溶性 受药物理化性质和pH影响 分子量小 脂溶性高 非解离型 极性小的 容易透过 存在离子障(ion trapping)现象,简单扩散脂溶性扩散,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 to penetrate the lip
8、id membrane because of their low lipid solubility,and passage will depend on the leakiness of the membrane related to the membranes electrical resistance.,Ka=,H+A HA,pKa=pH-log,A HA,A HA,10 pH-pKa=,酸性药：,碱性药：,pH和pKa决定药物分子解离多少,HendersonHasselbalch equation,A+H+HA,HAH+A,A HA,10pH-pKa=,pH=7,pH=4,1,1,102
9、,105,色甘酸钠(Cromolyn Sodium)：pKa=2,=107-2=105,A HA,10pH-pKa=,=104-2=102,弱酸性药物在酸性的环境中解离少,容易透过细胞膜在碱性的环境中解离多,不容易透过细胞膜弱碱性药物在酸性的环境中解离多,不容易透过细胞膜在碱性的环境中解离少,容易透过细胞膜,主动转运(Active transport),逆浓度梯度，耗能需要载体载体对药物有选择性饱和性 竞争性,易化扩散(Facilitated diffusion;Carrier-mediated diffusion)如：Glucose,Iron,5-fluorouracil,calcium,l
10、ead 需特异性载体顺浓度梯度，不耗能,膜动转运（cytosis/pinocytosis）,胞饮（pinocytosis）药物通过膜内陷小泡进入细胞胞吐（exocytosis）药物通过胞裂外排由细胞内转运至细胞外This mechanism is important for the transport of some macromolecules(e.g.insulin,which crosses the blood-brain barrier by this process),but not for small molecules.,二 药物在体内的存在形式,游离型（free）结合型（bou
11、nd）Transmembrane movement of drug generally is limited 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 节 药物的体内过程 Absorption,Distribution,Metabolism and Excretion,吸收,药物由给药部位进入全身血循环的过程存在于除静脉给
12、药方式外的所有其它给药途径途径：oral,sub-lingual,injection,inhalation,rectal,intra-vaginal,intra-nasal.topical?吸收快慢次序：血管内吸入舌下直肠肌肉内皮下口服皮肤,口服,The oral route(PO)is usually preferred.AdvantagesThe safest,most convenient,and most economicalDisadvantages Limited absorption of some drugsIrritation to the GI mucosaDestruct
13、ion of some drugs by digestive enzymes or low gastric pHIrregularities 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 administration and partially
14、 avoided by rectal administration.,小肠吸收,消化道吸收最主要部位吸收面积大血流量丰富，毛细血管壁通透性强药物与之接触时间长小肠既存在弱酸性环境，也存在弱碱性环境,胃肠道各部位吸收面积(m2)口腔 0.5-l.0直肠 0.02小肠 100,pH of Selective Body Fluids,血液循环示意图,首过消除(Presystemic/First-pass eliminaiton)药物由用药部位到达全身血循环前被组织器官代谢损失掉一部分的现象,First passmetabolism of drugs may occur as they cross t
15、he intestine or transit the livereg:nitroglycerinOther drugs may be destroyed before absorptioneg:penicillinSuch reactions decrease delivery to the target tissues,静脉注射给药（Intravenous）直接将药物注入血管不存在“吸收”过程，无“首关消除”肌肉注射和皮下注射(Intramuscular and subcutaneous injection)被动扩散过滤，吸收快而全 毛细血管壁孔半径40，大多水溶性药可滤过,注射给药特点,
16、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 absorption(3)no first pass metabolismB.Disadvantages include:(1)more difficult administration.(2)pain or necrosis at the si
17、te of injection(3)possibility of infection(4)toxicity from a bolus intravenous injection(5)necessity of dissolving the drug if given intravenously.,呼吸道给药,通过喷雾或气雾给药方式大颗粒粘附于呼吸道粘膜发挥局部作用小分子由呼吸道粘膜或肺泡上皮细胞吸收气体和挥发性药物直接进入肺泡，吸收迅速 肺泡表面积大（100-200m2）血流量大（肺毛细血管面积80m2）,舌下、直肠给药局部给药经皮给药：通过皮肤吸收产生局部或全身作用，药物吸收缓慢，作用持久经粘
18、膜吸收快于皮肤口腔、鼻、支气管、直肠、阴道皮下缓释给药,影响药物吸收的因素,药物理化性质和剂型首过消除给药途径甘露醇 ivgtt,po硫酸镁 ivgtt,po药物/食物相互作用Environmental pHBlood flow to the absorption siteTotal surface area available for absorptionContact time at the absorption surfaceExpression of P-glycoprotein,药物吸收定量参数,达峰时间（Tmax）达峰浓度（Cmax）曲线下面积（AUC）生物利用度（F）,2.分布（
19、Distributation),药物从血循环到达全身各个组织的过程规律：先“分布”，然后“再分布”分布部位存在选择性在血液循环和器官组织中浓度可达动态平衡前者间接反映靶器官药物浓度后者决定药物效应和毒性强弱血药浓度预测疗效强弱,脂溶性 组织器官血流量 组织结合、分布的选择性 血浆蛋白结合率 体液pH和药物离解度 体内屏障,Factors modulating drug distribution:,血浆蛋白结合(Plasma protein binding),可逆性（Reversible equilibrium）可饱和性（Saturable）DP（Non-permeable）不能透过细胞膜，不能
20、产生药效 非特异性和竞争性(Nonspecific&competitive）,对血浆蛋白质结合有相互作用的药物,思考,血浆蛋白结合率高的药物药量增加超过蛋白结合能力后，再增加药量，则.?血浆蛋白结合率高的药物联合应用时,.?血浆蛋白含量降低或变质后,.?,绝大多数药物采用此方式 扩散速度与脂溶性正相关 药物还需同时具有水溶性 受药物理化性质和pH影响 分子量小 脂溶性高 非解离型 极性小的 容易透过 存在离子障(ion trapping)现象,简单扩散脂溶性扩散,A+H+HA,HAH+A,A HA,10pH-pKa=,pH=7,pH=4,1,1,102,105,色甘酸钠(Cromolyn So
21、dium)：pKa-2,酸性,=107-2=105,A HA,10pH-pKa=,=104-2=102,总量100001,总量101,弱酸性药物在酸性的环境中解离少,容易透过细胞膜在碱性的环境中解离多,不容易透过细胞膜弱碱性药物在酸性的环境中解离多,不容易透过细胞膜在碱性的环境中解离少,容易透过细胞膜,弱酸性药物苯巴比妥中毒,用碳酸氢钠解救的理论依据？,问题：,血脑屏障(Blood-brain barrier,BBB),由毛细血管壁和N胶质细胞构成,大分子、脂溶度低的药物难透过有中枢作用的药物脂溶度高 也有载体转运，如葡萄糖可通过 可变：炎症时，通透性，大剂量青霉素有效,血脑屏障(Blood-
22、brain barrier,BBB),Plasma and cerebrospinal fluid concentrations of thienamycin following an intravenous dose(25 mg/kg)in normal or meningitis rabbits,55,代谢（生物转化,Metabolism,Biotransformation）：,Animals have evolved complex systems that detoxify foreign chemicals(xenobiotics)部位：主要在肝脏，其它如胃肠、肺、皮肤、肾步骤：分两
23、步反应，Phase I and phase IIBoth phases decrease lipid solubility,thus increasing renal elimination,56,The 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 i
24、nto more polar(hydrophilic)substances in the liver using two general sets of reactions,called Phase I and Phase II,I期反应（Phase I）：氧化、还原、水解、引入或脱去基团(-OH、-CH3、-NH2、-SH),II期反应（Phase II）：内源性葡萄糖醛酸、硫酸、醋酸等与药物或I期反应的代谢物结合生成极性很高的代谢产物,Phase I reactions convert lipophilic molecules into more polar molecules by in
25、troducing or unmasking a polar functional group,such as OH or NH2.Phase I metabolism may increase,decrease,or leave unaltered the drugs pharmacologic 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 Phas
26、e II reaction)and then hydrolyzed to isonicotinic acid(a Phase I reaction).,60,61,The two phases of drug metabolism,I期反应（Phase I）,are catabolic（氧化、还原、水解、引入或脱去基团(-OH、-CH3、-NH2、-SH)）the products are often more chemically/pharmacologically reactive and hence,paradoxically,sometimes more toxic or carcin
27、ogenic 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 forms combine with carbon monoxide to form a pink compound with absorption peaks near 450 nm 选择性低变异性、个体差异大可被诱
28、导或抑制,63,Examples of drugs that are substrates of P450 isoenzymes,64,Phase 2 reactions also normally terminate 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
29、rate of conjugation is 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 LiverMetabolism of Drugs a,质子泵抑制剂(PPIs)的代谢,CYP3A,CYP2C19,PPI
30、s,无活性代谢物,CYP2C19活性状况决定PPI血药浓度,我国汉族CYP2C19基因型分组的构成比,药酶诱导(Induction)：苯巴比妥、利福平，环境污染物等自身耐受性(引起耐药)交叉耐受性(同一药物代谢酶的底物),药酶抑制(Inhibition)：西米替丁、普罗地芬等竞争代谢途径而导致药物代谢酶被抑制。,无诱导,苯巴比妥诱导,苯并芘诱导,氯苯唑胺(骨松药)浓度（g/g组织）,时间（小时）,大鼠，注射诱导剂2次/日4日,药物代谢酶的活性可被诱导或抑制,问题奥美拉唑和氯吡格雷的作用机制各是什么？奥美拉唑为何会影响氯吡格雷的疗效？临床上为何特别关注药物间的相互作用？,4.排泄(Excreti
31、on),肾脏消化道 肺 皮肤 唾液 乳汁等,特点：多属被动转运，少数属于主动转运排泄或分泌器官中，药物浓度较高时既有治疗价值，又可能产生不良反应排泄器官功能变化对药物作用有影响,酸性 碱性,99%的H20和脂溶性药物,尿 1ml/min,肾小球滤过率(GFR)125ml/min,血浆流量 650ml/min,滤过 主动分泌 重吸收,药物及代谢物肾脏排泄方式,肾小球滤过血液中绝大部分游离药物可被滤过肾小管主动分泌遵循主动运输规律：竞争、饱和.肾小管被动重吸收符合被动转运规律：脂溶性、解离度小.改变尿液pH值影响重吸收,由肾小管主动分泌排泄的药物,尿液pH值对药物排泄的影响,Liver,Gut,F
32、eces excretion,Portal vein,胆汁排泄(biliary excretion)和肝肠循环,(Enterohepatic recycling),Bile duct,治疗胆道感染 有肝肠循环的药物作用明显延长中止肝肠循环,促进药物排出,可解毒(如强心苷)。,意义:,药物体内各过程的相互联系,体内药物的药量-时间关系 Time course of drug concentration,一、一次给药,血浆药物浓度(mg/L),药物浓度-时间曲线,常用血浆药物浓度-时间曲线药物及其代谢物体内过程之媒介药物作用靶组织、靶器官、各种体液和组织中药物浓度与血中药物浓度保持一定的比例关系采
33、集样本较其他方便,hrs,Plasma concentration,二、多次给药(Constant repeated administration of drugs)（1）稳态血药浓度(Steady-state concentration)目的：多次给药使血药浓度达有效范围,Examples of drugs where therapeutic drug monitoring(TDM)of plasma concentrations is used,85,药物在体内积蓄和从体内消除时程,87.5%94%97%,药物消除动力学 Elimination Kinetics,体内药物浓度因不断消除而随
34、时间不断变化,一级消除动力学(First order elimination kinetics)n=1 dC/dt=-kC,零级消除动力学(Zero order elimination kinetics)n=0 dC/dt=k,dC/dt=-kCn,k：消除速率常数(Rate constant for elimination),一、一级消除动力学 转运（消除）速度与浓度差成正比,t,二、零级消除动力学Ct=-k0t+C0 t1/2=0.5C0/k0,血浆药物浓度消除一半所需时间,一、消除半衰期（Half-life,T1/2）,零级消除动力学:t1/2=0.5 C0/k,一级消除动力学:t1/2
35、=0.693/Ke,t1/2,t1/2,t1/2,t1/2,t1/2,Slope(斜率)=-Ke/2.303,时间（h）,时间（h）,血浆药物浓度,血浆药物浓度,单位时间消除药量与浓度成正比半衰期不随浓度而变,单位时间消除药量不变半衰期随浓度而变,一级与零级消除比较,药物代谢动力学重要参数 Important Parameters in Pharmacokinetics,峰浓度 Cmax，达峰时间 Tmax,血管外给药后药物在血浆中的最高浓度值和出现时间，分别代表药物吸收的程度和速度,曲线下面积 AUC,时量曲线和横坐标围成的区域，表示一段时间内药物在血浆中的相对累积量,h,mg/ml,消除速
36、率常数（k or ke）,表示单位时间内机体能消除药物的固定分数或百分比，单位为时间的倒数。如某药的k0.2h-1，表示机体每小时可消除该小时起点时体内药量的20一级消除动力学时，k为一常数。是衡量药物消除快慢的一临床常用参数计算：k0.693/t1/2,消除半衰期（Half-life,T1/2）,血浆药物浓度消除一半所需时间 一级消除动力学T1/2=0.693/k与浓度无关，为恒定值,反映药物消除快慢固定剂量、固定时间给药经5个t1/2血药浓度达到稳态一次用药后经5个t1/2体内药量消除97%决定给药间隔时间肝肾功能 t1/2,意 义,零级消除动力学药物达一定浓度，机体消除能力达最大后的消除
37、动力学。给药剂量越大，半衰期越长 T1/2=0.5 C0/k,清除率(Clearance)来自生理学肌酐清除率的概念 单位时间内多少容积血浆中的药物被清除，反映肝肾功能 单位：L/h或ml/min CL=CL肾脏CL肝脏CL其它 计算公式：CL=D/AUC,表观分布容积(Apparent Volume of distribution),体内药物总量与血浆药物浓度之比 VdDC0Vd非体内生理空间,血浆3L 细胞间液11L 细胞内液32L,70kg体重，全身总体液量：46L,了解药物在体内分布 5L,分布于血浆 1020L分布于细胞外液 40L分布全身体液 100L则集中分布于某一器官,意义：推
38、测药物在体内的分布范围 Digoxin：0.5mg 0.78 ng/ml Vd=645 L 主要分布于肌肉（包括心肌，其浓度为血浓30倍）和脂肪组织 计算用药剂量：C=D/Vd,相对生物利用度：不同制剂AUC比较 F=(AUC受试制剂 AUC标准制剂)100%,生物利用度(Bioavailability)药物到达全身血循环内的相对量,绝对生物利用度：,特点及意义:1).受制剂(晶型、赋形剂、生产工艺等)、膜通透性、首过效应等影响。2).影响血药浓度，从而影响药效和毒性。3).是评价制剂优劣的主要参数之一。,Bioequivalence,Regulatory authorities-which
39、have to make decisions about the licensing of products that are generic equivalents of patented products-require evidence of 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.,Variation in oral absorption among different formulations of digoxin,三个药厂生产的地高辛,实例：某新药大鼠经静脉和皮下注射后药动学参数,Bioequivalence:Two related drug preparations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.,
