药理学教学汕头大学药物代谢动力学

1、会计学1药理学教学汕头大学药物代谢动力学药理学教学汕头大学药物代谢动力学用药用药药物在体循环药物在体循环中的浓度中的浓度药物在组织药物在组织中分布中分布药物代谢、药物代谢、排泄排泄药物在靶点的浓度药物在靶点的浓度药理作用药理作用临床反应临床反应毒副作用毒副作用药效药效药物代谢动力学药物代谢动力学 剂量剂量-浓度浓度药物效应动力学药物效应动力学 浓度浓度-效应效应分布消除吸收Elimination(消除消除): 代谢与排泄代谢与排泄Disposition(处置处置): 转运与转化转运与转化Section 1被动转运被动转运(Passive transport )Mechanisms of dru

2、g permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may also bind to

3、cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D).Neutral aspirinAspirin anionprotonPyrimethamine cationNeutral pyri

4、methamineProton10loglogHAAHAApKapHHAApHpKaHAAHKaAHHApKapH弱酸弱酸弱碱弱碱10loglogBHBBHBpKapHBHBpHpKaBHBHKaBHHBpKapHpH和pKa决定药物分子解离多少pHpKa)()(log非质子化的质子化的厚度通透系数面积21CC简单扩散滤过载体介导l主动转运l易化扩散Section 2胃酸stomach Acid微生物群microflora蠕动度motility消化酶digestive enzymes稀释dilution上腔静脉上腔静脉药物经肝静脉药物经肝静脉入体循环入体循环药物经门静脉药物经门静脉入肝脏入肝脏

5、小肠药物吸收小肠药物吸收Example: 硝酸甘油(Nitroglycerin)RouteOnseti.v.immediateSL1-3 minTransdermal40-60 min thenprotein, plasma ofamount totalis Ifdrug bound is DP drug free is DKDPDPPKDPPDDDPPDDTTD，+B药：98%Free A drug: 1%A药：99%血浆血浆蛋白蛋白Free A drug: 2%药效增强，药效增强，甚至毒性甚至毒性血脑屏障血脑屏障 (Blood-brain barrier, BBB)由毛细血管壁和N胶质细胞

6、构成脑部疾病用药时脑部疾病用药时如何使药物到达如何使药物到达脑内脑内代代 谢谢I I期期II II期期药物药物结合结合药物药物无活性无活性 活性活性 或或 结合结合结合结合药物药物亲脂亲脂 亲水亲水 排泄Many drugs are metabolized by two or more of these pathways. Note that two pathways, CYP3A4/5 and UGT, are involved in the metabolism of more than 75% of drugs in use. DPYD, dihydropyrimidine dehydr

7、ogenase; GST, glutathione-S-transferase; NAT, N-acetyltransferase; SULT, sulfotransferase; TPMT, thiopurine methyltransferase; UGT, UDP-glucuronosyltransferase. 芳香烃受体孕烷X受体雄烷氟喹诺酮异烟肼氟西汀环孢素环孢素伊曲康唑伊曲康唑利福平利福平麦芽汁麦芽汁LiverGutFeces excretionPortal veinBile duct胆汁排泄(biliary excretion)和肝肠循环(Enterohepatic recyc

8、ling)单次血管外给药后药物浓度-时间曲线Section 3)0(NKCdtdcN)0(NKCdtdcNeeetteteetettKteKKKtCCCCKCCKttKCCtKCCeCCCKdtdce693. 02lg303. 22ln5 . 0lg303. 2ln1303. 2lglglnln21000000，当0021000000005 . 05 . 0KCtCCKCCttKCCKdtdcCKdtdcttt，当消除消除 5单位单位/h2.5单位单位/h1.25单位单位/h消除消除2.5单位单位/h2.5单位单位/h2.5单位单位/hCKCVdtdcmmVm为消除最大速率；Km为Michae

9、lis常数，是最大速率一半时的浓度。为零级速率过程tVCCVCCVdtdcCKCVdtdcmtmmmm0服从一级速率过程。KCCKVKCVdtdcmmmmSection 4DDDKaKeCTlogCTabtKteCCKCdtdC0一级速率方程：微分方程：DDDKaDK12K21Ke或K10中央室周边室分布tttCPPPCCCBeAeCCKCKdtdCCKCKCKdtdC一级速率方程：微分方程：1221211210 A、B叫经验常数，代表分布相和消除相在纵轴的外推截距； 、为分布速率常数和消除速率常数，代表分布相和消除相的斜率。A+B分布相消除相Section 5AUC (Area Under

10、Curve, 曲线下面积曲线下面积)单位：单位：ng h/mL 反映药物体内总量反映药物体内总量Cmax (峰浓度峰浓度)l一次给药后的最高浓度一次给药后的最高浓度Tmax (达峰时间达峰时间)一次给药时，药物消除百分率取决于t1/2 ，经5个t1/2 ，药物基本消除；Constant repeated administration of drugs Steady-state concentration Aim to let MTCCssMECCss-max MECRATE IN = RATE OUTT1/212345502512.56.253.125502512.56.25502512.55

11、02550sum507587.593.596.5稳态稳态 约经约经4-54-5个半衰期达到个半衰期达到 达到时间与剂量、给药达到时间与剂量、给药间隔无关间隔无关稳态浓度稳态浓度 与剂量与剂量/ /药间隔相关药间隔相关 与生物利用度与生物利用度/ /清除率相关清除率相关波动度波动度 与给药间隔与给药间隔/ /t1/2相关相关 吸收慢减小波动度吸收慢减小波动度When a steady-state theophylline plasma level of 10 mg/L is desired. The smoothly rising black line shows the plasma conc

12、entration achieved with an intravenous infusion of 28 mg/h. The doses for 8-hourly administration (orange line) are 224 mg; for 24-hourly administration (blue line), 672 mg. In each of the three cases, the mean steady-state plasma concentration is 10 mg/L.Section 6o反映药物吸收的药动学参数1.曲线下面积(AUC)2.生物利用度(F)

13、3.达峰时间(Tmax)和达峰浓度(Cmax)o反映药物分布的药动学参数4.表观分布容积(Vd)o反映药物消除的药动学参数5.消除速率常数(Ke)6.半衰期(t1/2)7.清除率(CL)o多次用药的药动学参数8.稳态浓度(Css)9.波动度（一室模型静注）二室模型）KCdteCBACdtAUCKCttCCAUCKtniiniii0000111()(2)( 为体内药物总量AVKACLAAUCde95梯形面积法梯形面积法求求AUC0t%100DAF%100)()(血管内给药血管外给药AUCAUCF%100)()(对照药受试药AUCAUCFRouteBioavailability(%)Charact

14、eristicsIntravenous (IV)100 (by definition)Most rapid onsetIntramuscular (IM)75 to 100Large volumes often feasible; may be painfulSubcutaneous (SC)75 to 100Smaller volumes than IM; may be painfulOral (PO)5 to 100Most convenient; first-pass effect may be significantRectal (PR)30 to 100Less first-pass

15、 effect than oralInhalation5 to 100Often very rapid onsetTransdermal80 to 100Usually very slow absorption; used for lack of first-pass effect; prolonged duration of action99三个药厂生产的地高辛三个药厂生产的地高辛otherliverkidneysystemotherotherliverliverkidneykidneyREREREL/h)or ml/min (RE)n eliminatio of RateCLCLCLCLC

16、CLCCLCCLCCLAUCAAUCCVVKCLAUCCKKCAUCVKCCVKCAKCRECLCVACAVAKREddeeededeeddeeeeKssssKKdmssdemmsseCCeCeVFDCAUCVKFDCLFDCLRACLRECmaxmin0max11/21.min.max.ttssssssssssAUCAUCAUCCCCC的算术平均值和不是稳态时eeKKsssssssseeCCCC1122)min.max.min.max.（波动度（）Section 7Css-max MECn To maintain SS , the dosing rate must equal to the

17、rate of elimination. That is dosing rate = rate of eliminationTC : Target concentration CLTCDosing intervalFMD=时间时间(半衰期半衰期)MTCMEC时间时间(半衰期半衰期)MTCMECmmttmKmLKmLmKLLDDeDeDDteDDDFeDFDFeee22111112/12/12ln2/1时，当即每隔一个即每隔一个t1/2给药一次时，负荷量为维给药一次时，负荷量为维持量的持量的2 2倍。倍。CLVtCDVdd7 . 02/10FCCLMDFCVLDCCLksspdss0 thenprotein, plasma ofamount totalis Ifdrug bound is DP drug free is DKDPDPPKDPPDDDPPDDTTD，)0(NKCdtdcNT1/212345502512.56.253.125502512.56.25502512.5502550sum507587.593.596.5稳态稳态 约经约经4-54-5个半衰期达到个半衰期达到 达到时间与剂量、给药达到时间与剂量、给药间