药理学药物代谢动力学.pptx

1、,第二章 药代动力学,Pharmacokinetics,第二章 药物代谢动力学,(pharmacokinetics),研究药物的体内过程（吸收、分 布、代谢、排泄）及体内药物浓度随 时间变化的规律 .,术语,机体对药物的处置 : 吸收、分 布、代谢、排泄 (ADME), ,转运 : 吸收、分布、排泄 (ADE),消除 : 代谢 排泄 （ ME ）,Therapeutic Goal is to:,Achieve drug concentrations at the site of action (target tissue) that are sufficiently high enough t

2、o produce the intended effect,without producing adverse drug reactions.,Drug Administration,Absorption,Drug Concentration in Systemic,Drug in Tissues of Distribution,Drug Metabolism or Excreted,Circulation,Distribution,Elimination,Drug Concentration at Site of Action,Pharmacologic Effect Clinical Re

3、sponse,Toxicity,Efficacy,100 80,Drug at absorption site,60 40 20,Metabolites Excreted drug,Drug in body,Time,药物的转运,Drug Transport,Ch. 2,重点：脂溶扩散、离子障、 pH 对转运的影响,跨膜转运,被动转运,主动转运,膜动转运,简单扩散 易化扩散 原发性 继发性,胞饮,胞吐,脂溶扩散 水溶扩散,协同转运,交换转运,Transfer of drugs across Membranes,Extracellular,Carrier-mediated transport,S

4、imple diffusion (Lipid diffusion),Simple diffusion (Aqueous diffusion),1. Active transport,2. Facilitated diffusion,Intracellular,跨膜转运,被动转运,1.脂溶扩散 脂 / 水分配系数 扩散常数、膜面积、,浓度梯度；膜厚度 解离度（ Ka pH pKa),2. 水溶扩散 直径小于膜孔,3. 易化扩散 不耗能、需载体, ,主动转运 耗能、需载体,膜动转运 （胞饮、胞吐）耗能、不需载体,脂溶扩散,属被动转运 (passive transport) 顺浓差、不耗能、不需载体

5、、无饱和性、 无竞争性 。,大多数药物通过此种方式转运。,离子障 (ion trapping),非离子型药物可以自由穿透生物膜， 离子型药物则被限制在膜的一侧 .,Acidic drug: HA H,+,+ A,(ionized),Basic drug: BH,+, H,+,+ B (unionized),Ion trapping,Cell membranes are less permeable to ionized compounds,H+,H+,BH,+,B,A,-,HA HA,B,BH,+,A,-,H+,H+,Ionization depends on pH and pKa, H,+,

6、 A,Acidic drug ：,Ka =,HA, A ,pKa = pH - log,HA, A,10 =,pH-pKa,HA,Basic drug ：,pKa-pH,Example,Cromolyn Sodium ( 色甘酸钠 ) pKa=2, Acidic,Stomach ：,Plasma ：,pH=4 Total HAH,pH=7,+,+ A,A,+ H,+,HA Total,101 1,102,105,1 100001, A, A,10pH-pKa,=,10pH-pKa =,HA,HA,= 104-2,= 107-2,= 10,2,= 10,5,举例,苯巴比妥 ( 弱酸性 ) pKa

7、=7.4,根据 10 =A /HA, 当尿液为碱,pHpKa,性时， pH 值大于 pKa, A 增多，即,-, 解离型 多，重吸收减少，药物排泄 加快 , 中毒时碱化尿液。,EXAMPLE: ion trapping and higher concentrations of basic drugs in an acidic medium,Non-ionized basic drug would cross cell,Ionized basic drug would accumulate,membrane to the other side on the acidic side,B + H,+

8、,HB,+,B + H,+,HB,+,Mothers plasma pH 7.4,Fetal plasma pH 7.0 to 7.2 Breast milk pH 6.6,Slightly more acidic,某弱碱性药的 pKa 是 7.9 ，在 pH6.9 时其非 解 离 型 所占比例 接近那种情况,A 1 ,B 10 ,C 50 ,D 90 E 99 ,Key: B,药物转运体 (transporter),跨膜转运蛋白,摄取性转运体： PEPT1 ( 水溶性 - 内酰类口服 易吸收 ),外排性转运体： P-gp (P- 糖蛋白 ),西柚汁与钙通道阻断药的相互作用,Br J Clin

9、 Pharmacol. 2006 Aug;62(2):196-9,Aqueous diffusion,Small molecules diffusion through aqueous channels,Water solubility Small molecular, ,Diameter of aqueous channels in,Capillary wall: 4-8 （ =1010m ),Only for water, urea filtration,100 not permeable,Intracellular cleft: big hole,Intracellular cleft:

10、 40, all solute in blood are permeable except protein,Intracellular cleft,Ch. 2,Disposition of drug in the body,Absorption, Distribution, Metabolism and Excretion,1 Absorption,Transfer of a drug from its site of administration to the blood stream,Oral ingestion,Major site: intestine,Longer transit t

11、ime = 3 hours Larger surface area of villus Abundant blood flow, ,pH5-8 good for most of drugs,Ficks Law of Diffusion,Flux (molecules per unit time),AreaPermeability coefficient, (C1 ,Thickness C2),Oral cavity 0.5-l .0 m Stomach 0.1-0.2 m Small intestine 100 m Large intestine 0.04-0.07 m Rectum 0.02

12、 m,2, ,2,2,2,2,First pass effect (first pass,metabolism),Metabolizing enzymes in the intestinal wall,and/or in the liver,Intestines,Drug molecules,Very little or no drug reaches the,Liver general circulation,Portal circulation,Intramuscular pulmonary,2,capillary area = 80 m2,Rapid, no first pass eff

13、ect, directly reach desired site of action (asthma, COPD),Transdermal,Transdermal skin patches-,Lipid soluble drugs can be absorpted,via skin,Nifedipine,Glycerol trinitrate,2 Distribution,Process by which a drug reversibly leaves the blood stream and enters the interstitial or cellular fluids of the

14、 body.,Receptor,Free bound,Free drug, Bound Drug,Tissue Free bound,Blood,Metabolites Excretion,Factors that affect drug distribution,Physical and chemical characteristics of the drug (lipid to water partition coefficient),Cardiac output B. phenobarbital is discontinued; C. phenobarbital dose is incr

15、eased; D. A and C;,E.None of the above.,Enzyme inhibition,Slows down metabolism, decreases drug clearance, increases concentration of substrates,Consequences of Inhibition,Increase in the plasma concentration of,parent drug,Reduction in metabolite concentration,Exaggerated and prolonged,pharmacologi

16、cal effects,Increased likelihood of drug-induced toxicity,酮康唑、红霉素,CYP3A4,特非拉定 前药,特非拉定酸,抗组胺作用 心脏毒性低,影响心肌细胞的钾 通道，使复极减慢 ， QTc 延长，最终 可发生尖端扭转型 室性心动过速而致 死,85%,氯 吡 格 雷 的 活 化,CYP2C19 是氯吡格雷 活化的重要 催化酶,15%,_,奥美拉唑,活性代谢物,2009 年 11 月 FDA 警告信息, ,不推荐任何情况下联合服用氯吡格雷和奥美拉唑（同时服或 间隔 12 小时服用均应避免）。目前 FDA 还没有足够证据来 阐明氯吡格雷和其它

17、PPI 间的相互作用。,接受氯吡格雷治疗的患者，如果需要，可以选择组胺 H 受,2,体拮抗剂如雷尼替丁、法莫替丁、尼扎替丁用于抑酸治疗， 但需禁用西米替丁（它是 CYP3A4 抑制剂，干扰氯吡格雷抗 血小板效应）。,接受氯吡格雷治疗的患者如果正在服用或准备开始服用奥美 拉唑（包括 OTC 类药物）时，需要向医生咨询，谨慎评估 风险。,/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationf orHeathcareProfessi

18、onals/ucm190784.htm,4. Excretion,The process by which a drug or metabolite is eliminated from the body,The ways by which a drug is,Routes of excretion,excreted by the kidney,Glomerular Filtration Rate (GFR): 125ml/min,Kidney (most important),Urine 1ml/min,Biliary tract and the feces,Others: expired

19、air, sweat, saliva, tears and breast milk,Plasma flow 650ml/min,Acid Base 99% of H 0 +,2,organic anion Organic transporting Cation,Lipid soluble drugs,polypeptide, Transporters,OATP,OCT,Filtration Active secretion Reabsorption,Example ：,Aspirin is an acid with a pKa of 3.5,If the urinary pH is 2.5 t

20、hen the ratio of,ionised:unionised drug is 0.1 ,i.e. 90 % of the drug is unionised, it crosses membrane readily and will be reabsorbed.,If the urinary pH were 5.5, what is the result?,Biliary Secretion,Biliary excretion,Liver,首过消除 : 初次经过肠壁肝脏时被代谢清除,18425,51,Bioavailability,Destroyed Not,Destroyed Des

21、troyed,in gut absorbed by gut wall by liver,To,systemic circulation,Dose,表观分布容积,氯喹： Vd = 13000 L/70kg,18425,53,Acidic drugs,Basic drugs Amphoteric drugs,Neutral drugs,plasma 4 L,Basic drugs,accumulate in tissue high Vd,Vd of Selected drugs,Drug,Volume (L/70kg),Intercellular 10 L,Mepacrine （阿的平） Chlo

22、roquine （氯喹） Amphetamine （苯丙胺） Propranolol （普萘洛尔） Theophylline （氨茶碱） Tolbutamide （甲苯磺丁 脲）,40000 17000 300 250 30,Intracellular 28 L,6,Total ： 42 L,给药方案设计举例,某药的治疗浓度范围为 25-50mg/L, 已知 其 Vd=10 L, 试拟定合适的给药剂量, ,D0=250 500 mg,房室模型的概念 (1),血 中 药 量,0,时间,一室模型,房室模型的概念 (2),血 中 药 量,0,时间,开放性一室模型,房室模型的概念 (3),血 中 药

23、量,0,时间,二室模型,房室模型的概念 (4),血 中 药 量,0,时间,开放性二室模型,房室模型的概念,一室模型, ,给药后药物瞬间在全身各体液和组织中分布达到平衡 ；,血药浓度呈单相下降； 临床上大多数药物可以此模型近似计算；, ,二室模型,将机体分为分布速率较快的中央室与较慢的周边室；,血药浓度呈双相下降：分布相 ( 相 ) 、消除相 ( 相 ) ；,进行药剂的动力学研究此模型较准确；,生理模型,将机体各组织器官作为独立的多个房室；,一般只有理论意义，实际应用较少；,100.0 10.0 1.0,一室模型 二室模型,0.1,100.0,分布相,10.0 1.0,消除相,0.1,0,4,8

24、,12, (h),Elimination kinetics,Rate constant for elimination,dC/dt = - kCn,Zero order,First order elimination kinetics n = 1 dC/dt = - kC,First order,Zero order,Zero order elimination kinetics n = 0 dC/dt = k,First order,Time,速率过程,一级动力学 ( 恒比消除 ),药物在单位时间内以恒定的比例转运或消除； 单位时间内的消除速度与当时的血药浓度呈正比； 大多数药物在治疗剂量下

25、符合一级动力学过程；, ,零级动力学 ( 恒量消除 ), ,药物在单位时间内以恒定的药量转运或消除； 每一时间的消除速度与当时的血药浓度无关；,非线性速率 (Michaelis-Menten 动力学 ),药物在高浓度时为零级速率 ( 恒量 ) 过程； 药物在低浓度时以一级速率 ( 恒比 ) 过程；,半衰期 (t1/2):,血药浓度下降一半所需的时间,反映药物的消除速度；, ,确定给药间隔的依据；,测算达到稳态的时间及药物清除时间；,t = 0.693/ke,1/2,清除率 (CL),单位时间内能把多少容积血中的药物全部清除,(L/h, ml/min).,CL = 消除速度 / 血药浓度,据此可

26、推算 给药速度,消除速度 CL 血药浓度,Mixd elimination kinetics,Low concentration (10mg/L): First order,High concentration (10mg/L): Zero order,Saturation of metabolizing enzyme,2. Multiple dose,Constant repeated administration of drugs To produce a Css MEC and MTC,5 half-life, 90% of steady-state concentration is r

27、eached in 3.3 half-lives,Css-max MEC,Drug accumulation and elimination,90%,87.5% 94% 97%,3.3,等量等间隔用药 ,T =24h,V =200L, 剂量单位 :mg,0.5,d,D = 800(A),D = 400(B),D = 200(C),0,0,0,qd,bid,qd,1st,2nd,t0.5 1,Cp,Cq 4.000 2.000 6.000 3.000 7.000 3.500 7.500 3.750 7.750 3.875 7.875 3.938 7.938 3.969 7.969 3.984,C

28、p,Cq,Cp,Cq,Cp,Cq 1.000 0.500 1.500 0.750 1.750 0.875 1.875 0.938 1.938 0.969 1.969 0.984 1.984 0.992 1.992 0.996,2.000 1.414 4.414 3.121 5.621 3.975 6.225 4.402 6.527 4.615 6.678 4.722 6.753 4.775 6.791 4.802,3.414 2.414 5.121 3.621 5.975 4.225 6.402 4.527 6.615 4.678 6.722 4.753 6.775 4.791 6.802 4

29、.810,2 3 4 5,6 7,8,Css = 5.76,5.76,2.88,8 6 4 2 0,A,B,C,0,2,4,6,8, ( ),？ P32 ，假定按 半衰期给药， .,多次用,的概念,等量等间隔给药时 , 血浓逐渐上升 , 经 5 个半衰期后达到稳态水平； 进出平衡：在一个给药间隔内消除的药量与 进入体内的药量相等；, ,水平波动：血药浓度在平均浓度上下波动；, 坪值 (plateau) 浓度 峰谷平均,等量等间隔多次给药时血药浓度,平均稳态浓度高低每个半衰期给药总量 血浓波动大小每次药量 ( 总量不变 ) 达坪时间只与 t 有关 , 恒为 5 个 t ., ,1/2,1/2,L

30、oading dose,Utilized when a therapeutic level is desired quickly and an initial larger dose is administered followed by substantially smaller maintenance doses (may increase risk of toxicity and adverse effects).,Time,Time,重要的 PK 参数,吸收： AUC, Camx, Tmax, BA 分布： Vd, 房室数, ,消除： t Cl,1/2,Chapter 4,Factor

31、s affecting drug response,Section 1,Ch. 4,Pharmaceutical Factors,Pharmaceutical Factors,1. Dose, formulation, route of administration 2. Drug Interactions,（ 1 ） Pharmacokinetic interactions ：,chemical or physical;,GI absorption;,protein binding/distribution;,metabolism (stimulation/inhibition);,excr

32、etion (pH/transport processes);, changes in pH or electrolytes.,（ 2 ） Pharmacodynamic interactions ：,receptor (potentiation/antagonism,Section 2,Ch. 4,Biological Factors,Many factors affect drug response,1. Age,Age related change: 1. liver metabolism; 2. renal elimination; 3. body composition,liver

33、metabolism- less amount of drug metabolizing enzymes in, ,newborn infants,Older people usually take more drugs, also may have more difficulty following complicated instructions for taking drugs.,1. Age,Developmental profile of hepatic drug metabolizing enzymes,CYP3A7,Most drug-metabolizing enzymes,Enzyme level,Birth,Adulthood,Elderly,Age,2. Gender,Women have more CYP3A in the liver, ,Estrogen and progestin inhibit CYP450 leading to a lower CL of drugs in women,Women tend to take more medications, including dietary supplements, than men,3. Body Size / Obesit