药代动力学总论

Basic pharmacokinetics,高晓霞中医药现代研究中心2013.10,主要内容,药代动力学总论房室模型计算生物样品测定方法学验证相关软件介绍专题血清药物化学生物利用度与生物等效性药动学-药效学相关性研究药物代谢与代谢组学结合研究,作业,考试文献讲读英文二区以上，如CDM、DMD（降3区）等药物代谢等相关内容文章顶级杂志不相关也可，如Nature、Science、Cell等,What is pharmacokinetics?,Pharmacokinetics is the mathematics of the time course of Absorption, Distribution, Metabolism, and Excretion (ADME) of drugs in the body. 药物代谢动力学是定量研究药物在生物体内吸收、分布、代谢和排泄规律，并运用数学原理和方法阐述血药浓度随时间变化的规律的一门学科,Definition,体内药物浓度随时间变化的动力学规律,从给药部位进入全身循环,(1) 口服给药 (Oral ingestion),吸收部位,停留时间长，经绒毛吸收面积大,毛细血管壁孔道大，血流丰富,pH5-8，对药物解离影响小,主要在小肠,1吸收 (Absorption),胃肠道各部位吸收面积(m2) 口腔 0.5-l .0直肠 0.02胃 0.1-0.2小肠 100大肠 0.04-0.07,Fick扩散律 （Ficks Law of Diffusion）,流量 (单位时间分子数) =,面积 通透系数厚度,首过消除(First pass eliminaiton),（2）肌肉注射和皮下注射 (Intramuscular and subcutaneous injection) 被动扩散过滤 吸收快而全,（3） 呼吸道吸入给药 (Inhalation) 气体和挥发性药物（全麻药）直接进入肺泡，吸收迅速。因为： 肺泡表面积100-200m2血流量大(肺毛细血管面积80 m2 ),（4）经皮给药 (Transdermal) 脂溶性药物可通过皮肤进入血液。 硝苯地平贴皮剂、硝酸甘油。,改善吸收的方法？,剂型与给药途径口服注射：蛋白等生物药口服舌下含片：硝酸甘油减小毒副反应普通片剂肠溶片：阿司匹林、双氯芬酸钠,药物从血循到达作用、储存、代谢、排泄等部位,2分布 (Distribution),Free drugBoundDrugMetabolites,ReceptorFreebound,TissueFreebound,Excretion,Blood,脂溶度 局部 pH 和药物离解度毛细血管通透性组织通透性转运蛋白量血流量和组织大小 血浆蛋白和组织结合,Factors modulating drug distribution,血浆蛋白结合(Plasma protein binding),Reversible equilibriumSaturableDP: Non-permeableNonspecific & competitive,Plasma proteins Albumin: Weak acids alpha-acid glycoprotein: Weak basesEffects of plasma protein binding Free fraction: active, excreted, metabolizedthe more binding, the less active drug the more binding, the less excreted and metabolized: “longer half-life”,Drug A: 1000 molecules,99.9% bound,1 molecules free,100-fold increase in free pharmacologically active concentration at site of action. Effective TOXIC,+ Drug B with 94% bound,90.0% bound,100 molecules free,Drug interaction of plasma protein binding,血脑屏障 (Blood-brain barrier, BBB),由毛细血管壁和N胶质细胞构成,胎盘将母体与胎儿血液分开，也起屏障作用，故称胎盘屏障。 药物通过胎盘的转运方式主要是简单扩散。大多数药物均能进入胎儿。,胎盘屏障 （Placental barrier）,分布的指导,区分疾病部位给药抗生素、消炎：上呼吸道感染、牙疼、脑膜炎、一般伤口、胃肠道疾病肝肾毒性评估代谢、排泄的主要途径靶向制剂增强药物在靶部位的药效、减小药物毒性,3. 代谢（生物转化) Metabolism, Biotransformation,代谢部位： 主要在肝脏，其它如胃肠、肺、皮肤、肾,Phase I,药物,结合,药物,无活性,活性或,药物,亲脂,亲水,排 泄,氧化、还原、水解引入或脱去基团(-OH、-CH3、-NH2、-SH),Phase II,结合,结合,内源性葡萄糖苷酸、硫酸、醋酸与药物或I期反应代谢物结合,代谢步骤和方式,药物氧化代谢 (Oxidation),细胞色素P450单氧化酶系,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。,药物代谢酶的活性可被诱导或抑制,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,代谢的指导,新药的发现代谢物活性与毒性测定非那西丁、对乙酰氨基酚（扑热息痛）减少代谢、减小肝肾组织负担药物合用种族差异、家族差异代谢酶活性差异指导用药,排泄途径：肾脏 (主要)消化道肺皮肤唾液乳汁等,4. 排泄（Excretion),Liver,Gut,Feces excretion,Portal vein,胆汁排泄(Biliary excretion)&肝肠循环,(Enterohepatic recycling),Bile duct,消 化 道 排 泄,排泄的指导,药物开发氨苄西林与丙磺舒合用，竞争肾小管重吸收,体内药物的药量-时间关系Time course of drug concentration,第二章,第 三 节,一、单次给药,Time (min),Plasma aspirin concentration (mg/L),Cmax,Tmax,单次静脉注射,单次口服,hrs,Plasma concentration,AUC,Area under curve,二、多次给药 Constant repeated administration of drugs,稳态血药浓度 (Steady-state concentration) 多次给药旨在稳态血药浓度达有效浓度范围: MTCCssMEC,Css-max MEC,需4-5 half-life,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,第二 章,第 四 节,体内药物浓度因不断消除而随时间不断变化,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),低浓度 (10mg/L): 零级,混 合 速 率 动 力 学,药物代谢动力学重要参数Important Parameters in Pharmacokinetics,第二 章,第 五 节,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 =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,半 衰 期（Half-Life）血浆药物浓度或体内药物总量减少1/2所需时间，反映药物消除过程。,T1 /2 0.693/k,T1/2停药后体内残留量150%312.553.125,TIME TERMS (UNIT: TIME),t Tt t0ttmaxtdurt,time since administration of doseduration of zero-order inputtime since cessation of zero-order inputlag timeelimination half-life (“biological half-life”)time when maximum amount or concentration occursduration of effective pharmacological responsedosing interval (greek theta),单位时间内机体清除药物的速率。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,二、消除率（ Clearance，CL ）,体内药物总量和血浆药物浓度之比 VdDC,三、表观分布容积（Volume of distribution）,设想药物均匀分布于各种组织与体液，且浓度与血液中相同，在这种假设条件下药物分布所需容积。数学概念，并不代表具体的生理空间。给药剂量或体内药物总量与血药物浓度的比例常数,血浆 3 L,细胞间液 12 L,细胞内液 27 L,体液总量、组成和药物Vd的关系,Acidic drugs,Basic drugs,Amphoteric drugs,Neutral drugs,碱性药物因在组织内蓄积而致高Vd值,总体液：42 L,推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：Vd=D/C,Vd的临床应用意义,VOLUME TERMS (UNIT: VOLUME),Vd apparent volume of unchanged drug distribution in compartmentVm apparent volume of metabolite distribution in compartmentVw physiological volume of plasma water,药物到达全身血循环内的相对量和速度,2. 吸收速度： 比较 Tmax,绝对生物利用度：,F =, 100%,AUC血管外,AUC静注,不同制剂AUC比较 F = (AUC受试制剂 AUC标准制剂) 100%,四、生物利用度（ Bioavailability ）,1. 吸收相对量,相对生物利用度：,同一受试人群口服0.5mg 地高辛（digoxin）,A制药公司产品,B制药公司生产的两批产品,1.10 Pharmacokinetic Symbolism,AMOUNT TERMS (UNIT: MASS)D dose (or maintenance dose)CONCENTRATION TERMS (UNITS MASS/VOLUME)Cb concentration of drug in blood at any timeCp concentration of drug in plasma at any timeCm Concentration of metabolite in plasma (or blood) at any time(Cp)ss “average” steady-state concentration of drug in plasma during a dosing interval(Cp)max maximum concentration of drug in plasma(Cp)min minimum concentration of drug in plasmaMEC minimum effective concentration of drug or metaboliteMTC minimum toxic concentration of drug or metabolite,多剂量给药的有关参数,Css,max=FD/Vd(1-e-) Css,min=FD e-/Vd(1-e-) Css,avg(Cp)=AUCss/= (FD/CL)/DF(%)=(Css,max - Css,min)/ Css,avg=,AUC (Css,av之上）,AUC (Css,av之下）,浓度,给药间隔时间（h),AUCss,AUC (单剂量),AUC (1,t),小时,浓度,Css,max,Css,min,RATE CONSTANT TERMS (UNIT: RECIPROCAL（ 倒数）TIME (*), MASS/TIME(*),K ke Kd, Ki apparent first-order rate constant for elimination, Summation of all the ways the drug is eliminated (*)ka apparent first-order rate constant for absorption (*)ku, kr apparent first-order rate constant for urinary (renal) excretion of unchanged drug (*)km apparent first-order rate constant for metabolism of unchanged drug (*)k0 zero-order input rate constant (*),CLEARANCE TERMS (UNITS: VOLUME/TIME),Cl total body clearance (TBC)Clr renal clearance (RC)Clm metabolic clearance (MC)Clcr creatinine clearanceClH hepatic clearance (HC),单位时间内有多少毫升血中的药物被清除正确估算药物从体内消除速度的唯一参数,总清除率（CL, Total body c1earance）,OTHER TERMS,AUC area under the plasma concentration-time curve (units: time * mass/volume)AUMC area under the first moment of the plasma concentration-time curve (units: time2 mass volume)MRT Mean Residence Time (units: time )MAT Mean Absorption Time (units: time )E intensity of pharmacological effectEmax maximum intensity of pharmacological effectF fraction of administered dose ultimately absorbed,AUC0 指药物从零时间至所有原形药物全部消除这一段时间的药-时曲线下总面积，反映药物进入血循环的总量,药-时曲线下面积（AUC）,计 算 方 法,方法一：根据 A、B、各值计算,方法二：梯形面积法（trapezoidal rule）,Time,Blood Drug Concentration (mg/L),Area 1,Area 2,AUC0：以最小二乘法先求，再按下式算出,AUC0= AUC0n+ Cn/,总面积各间隔时间内梯形面积和,AUC0n=(1/2)(C1+C2)(t2-t1)+ (1/2)(C2+C3)(t3-t2) + + (1/2)(Cn-1+Cn)(tn-tn-1),CHAPTER 2,Mathematics Review,BASIC MATHEMATICAL SKILLS OBJECTIVES,1. Given a data set containing a pair of variables, the student will properly construct (III) various graphs of the data.2. Given various graphical representations of data, the student will calculate (III) the slope and intercept by hand as well as using linear regression.3. The student shall be able to interpret (V) the meaning of the slope and intercept for the various types of data sets.4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic manipulations.5. The student shall demonstrate (III) the proper calculus procedures of integration and differentiation.6. The student shall demonstrate (III) the proper use of computers in graphical simulations and problem solving.7. Given information regarding the drug and the pharmacokinetic assumptions for the model, the student will construct (III) models and develop (V) equations of the ADME processes using LaPlace Transforms.8. The student will interpret (IV) a given model mathematically.9. The student will predict (IV) changes in the final result based on changes in variables throughout the model.10. The student will correlate (V) the graphs of the data with the equations and models so generated.,A10n Where A is a value between 1 and 10, and n is a positive or negative integerAEn2.28E4 =2.28 104 = 22800,有效数字,An where A is a number, which may be p