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Transcript
Chapter 2 Pharmacokinetics Department of pharmacology M. Y. Liu Pharmacokinetics Transmembrane transport Processes of drug in the body Basic concepts of pharmacokinetics Part 1 Transmembrane transport of drugs LOCUS OF ACTION “RECEPTORS” Bound ABSORPTION Free TISSUE RESERVOIRS Free Bound Free Drug Bound Drug SYSTEMIC CIRCULATION BIOTRANSFORMATION EXCRETION The structure of cell membrane? How to transport it? Transmembrane transport Procedure of permeating through the various barriers Such as: various cell membrane the walls of the capillary the walls of the intestine blood-brain barrier placental barrier Ability that the drug permeates through various membranes Two types of transmembrane transport Passive transport (down hill movement) According to the concentration gradient of the permeating drug, the direction of diffusion was from higher concentration to lower concentration. Small molecules: membrane pores Large molecules: lipid diffusion Not requiring energy Having no saturation Having no carriers Not resisting competitive inhibition Affecting factors : the size of molecule lipid solubility polarity degree of ionization the PH of the environment such as: fluid of body fluid in cell blood, urine Generally speaking The drugs which are Unionized, low polarity and higher lipid solubility are easy to permeate membrane. The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane. Effect of the environment PH on drug transportation Most of drugs are weak acids or weak bases. The ionization of drugs may markedly reduce their ability to permeate membranes. The degree of ionization of drugs is determined by the surrounding pH and their pKa. For acids: Handerson-Hasselbalch Equation The pKa is the pH at which the drug is 50% ionized. For bases: pH和pKa算术差的变化, 就会导致解离与非解离药 物浓度差的指数变化,因 此pH的微小变化将显著的 影响药物的解离和转运。 When the pH is different from the intracellular and extracellular membrane and the passive transport of weak acid/base drugs are in the balance, the drug concentration of intracellular and extracellular membrane are compared as below: eg. For weak acid drug whose pKa is equal to 5.4 unionized plasma pH=7.4 [HA] 1 Gastric juice pH=1.4 [HA] 1 ionized [A-] 100 [A-] 0.0001 When drug concentration of the intracellular and extracellular membrane are balanced, the total concentration isn’t equal; while the concentration of unionized drug are same . total 101 1.0001 pKa= 3.4 When the pH of the intracellular and extracellular are not equal, the total concentration of the drug in the two sides of membrane are given by the equation as below: For acid: For base: Q:What kind of drugs can be excreted to the latex which pH is tend to acidity? The other forms of passive transport Filtration: water solubility small molecular Facilitated transport: (in fact it is a kind of passive transport) Transport from high concentration to low concentration Not requiring energy Requiring carriers eg the absorption of Vitamin B12 from GI tract The transportation of Glucose to the intra cellular membrane of red blood cells. Active transport permeating membrane from lower concentration to higher concentration. Requiring energy Requiring carriers Be Saturable H aving competitive inhibition Such as : peptide, amino acid The conditions which need active transport Na+-K+-ATPase The transmitters were concentrated in the vesicle. The excretion and secretion of renal tract Active transport can concentrate drugs in certain organ or tissue (the iodine pump ) Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Diffusion Bulk Flow Endocytosis Ion Pair Facilitated Transport Active Transport Sugars, amino acids, vitamins Diffusion Bulk Flow Most drugs are Ion Pairabsorbed and distributed by Facilitated Transport diffusion. Endocytosis Active Transport 药物代谢动力学 The processes of drugs(ADME) Pharmacokinetics • movement of drugs in the body • what the body does to the drug “ADME” Absorption Distribution Metabolism Excretion The disposition to drugs by living systems can be divided into four related duration: 吸收(Absorption) 分布(Distribution) 代谢(Metabolism) 排泄(Excretion) ADME 系统 Metabolism + Excretion = Elimination Absorption + Distribution + Excretion = Transportation Metabolism= Transformation Absorption is the transfer of a drug from its site of administration to the blood stream. Characters: Most of drugs are absorbed by the way of passive transport. Intravenous administration has no absorption. The absorptive speed affects the time of appearing effect. The absorptive extent affects the intensity of action. Factors affecting absorption: drug properties: lipid solubility、Molecular Weight,polarity,etc. Routes of Administration (important): Enteral; parenteral Other: Blood flow to the absorption site; Total surface area available for absorption Contact time at the absorption surface Affinity with special tissue Enteral administration Oral Sublingual Rectal Oral administration First Pass Elimination (首关消除,首关代谢,首关效应) Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a Result, the concentration of drug in the systemic circulation will be reduced. FIRST PASS ELIMINATION Metabolism in the liver Buccal cavity Stomach Intestine Rectum Portal vein Vena cava Sublingual Administration (硝酸甘油) Rectal Administration (水合氯醛) Buccal or rectal administration are ways to by-pass the liver and avoid “first pass” Buccal cavity Buccal Stomach Vena cava Intestine Rectum Rectal Parenteral Inhalation 注射给药 静脉内 肌内 皮下 intravenous (IV) intramuscular (IM) subcutaneous (SC) other:intranasal(经鼻给药), intraventricular(心室 内给药), Transdermal(经皮给药) Intravenous administration has no absorption phase. According to the rate of absorption: Inhalation→Sublingual→Rectal→intramusc ular→subcutaneous→oral→transdermal Example: 硝酸甘油(Nitroglycerin) Route Onset IV immediate SL 1-3 min Transdermal 40-60 min Distribution Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. 药物的体内过程 分布 •Factors affecting drug distribution: •Blood flow •Capillary permeability •Capillary structure •Drug structue •Binding of drugs to proteins •Most drugs found in the vascular compartment are bound reversibly with one or more of the macromolecules in plasma. •Many acidic drugs bind principally to albumin, while basic drugs frequently bind to other plasma proteins such as lipoproteins and α1-acid glycoprotein (α1-AGP)。 药物与血浆蛋白结合(Protein binding) Characters: Drugs ordinarily bind to protein in a reversible fashion and in dynamic equilibrium. Those bound to protein are called bound drug, and those unbound to protein are called free drug. Only the unbound drugs can diffuse through the capillary wall, produce its systemic effects, be metabolized and be excreted. Bound drugs lose pharmacological activity momentarily, and act as a drug reservoir. Having saturation and competitive inhibition. Patient with low plasma protein (uraemia, hepatic disease) or old people with low albumin in plasma ,their percentage of protein binding may be changed, amount of unbound drug increases, effect precipitate. interaction When the two kind of drugs that possess the higher protein binding rate are associated for clinical using, the drug interaction may occur. If the amount of unbound drug displaced from plasma protein increases, the unbound drug concentration and effect also increases, and perhaps, produce toxicity. Such as: phenylbutazone (保泰松) Dicoumarin (双香豆素) How to salvage the toxic effect of barbital drugs? With NaHCO3 Alkalizing plasma to force the weak acidic drug (barbital drug) from brain to plasma. Alkalizing urine to increase the excretion of the drugs Biological barriers bound/ ionized drug can not pass through the BBB! 血脑屏障 Blood Brain Barrier • • 毛细血管内皮 细胞联结紧密, 管壁外被星型 胶质细胞包围。 炎症可改变通透性 14C-Promazine 14C-Promazine Quaternary Analog + 胎盘屏障 Placental barriers 生物膜屏障(membrane barriers) having no barrier effect on drug transport, but the pregnant women should especially pay attention. Blood-eye barriers Metabolism: most often eliminated by biotransformation Drugs are and /or excretion into the urine or bile. The liver is the major site for drug metabolism. Two phase of metabolism: Phase I:oxidation (氧化) 、hydrolysis (水解反 应 ) 、reduction(还原) Phase Ⅱ:conjugation(结合反应 ): glucuronic acid(葡萄糖醛酸) sulfuric acid glycin (甘氨酸) Changes after metabolism: The pharmacological activity of the drugs is decreased or lost, while certain drugs must metabolize to exert the reaction. Variety of drug activity after biotransformation: A active drug B inactive drug inactive metabolites active/enhanced activity Such as : P-450 Cyclophosphamide(环磷酰胺) blood tumor aldophosphamide(醛磷酰胺) Phosphamide mustard(磷酸胺氮芥) C active drug Phenacetin非那西丁 active product Acetaminophen (paracetamol) 对乙酰氨基酚(扑热息痛) (prototype drug or parent drug) D no toxic or less toxic drug toxic metabolites Isoniazid(Rimifon) Acetylisoniazid INH 异烟肼 Acetyl INH mutagenicity致突变 teratogenicity致畸变 carcinogenicity致癌 hepatotoxicity肝毒性 E consequent 1)Lipophilic xenobiotics (or drugs) are transformed to more polar and hence more readily excretable products. Lipophilic drug hydrophilic compound (lipid soluble water soluble) 2)Large molecule small molecule Enzyme system classification: Special enzyme: AChE, MAO Unspecial enzyme: Cytochrome P450 Enzymes properties: low selectivity and specificity saturation large variability induced or inhibited by drugs---enzyme induction or enzyme inhibition Induction and inhibition of enzyme Some drugs can increase the rate of synthesis of cytochrome P450 enzymes . This enzyme induction can enhance the clearance of other drugs. Inducing agents are: rifampicin(利福平), carbamazepine(卡马西平), phenobarbital(苯巴比妥), phenytoin(苯妥英) Other drugs can inhibit cytochrome P450 enzymes. This is usually seen rapidly after drug exposure. Enzyme inhibiting agents are: Cimetidine(西咪替丁) chloromycetin (氯霉素) Isoniazid(异烟肼) excretion Excretion is a transport procedure which the prototype drug (or parent drug) or other metabolic products are excreted through excretion organ or secretion organ. Principal organs: Kidney,biliary system, lungs, intestines, milk, skin, sweat glands Renal Excretion Filtration Secretion Reabsorption Renal excretion glomerular filtration Protein bound drugs are not filtered !! Reabsorption high lipid-soluble ,lower polar. unionized drug easy to reabsorb high water–soluble, high polar ionized drug uneasy to reabsorb Active secretion of tubule Changing pH of tubular lumen fluid, may change absorption extent of drug in urine. acidic urine = alkaline drugs eliminated acid drugs reabsorbed alkaline urine = - acid drugs eliminated - alkaline drugs absorbed renal disease/ decreased clearance affects drug dosage affect of uric pH on dissociation of drug weak acid drug dissociation large weak basic drug dissociation large weak acid drug dissociation small weak basic drug dissociation small alkaline urine excretion accelerate acid urine excretion fast acid urine excretion reduce alkaline urine excretion slow ※ competitive inhibition when two drug pass through same pathway, using same carrier ,competitive inhibition can occur. For example 1 Penicillin and Probenecid Using acid pathway Decreasing excretion of penicillin Increasing action duration of enicillin 2 Ethacrynic acid and uric acid Decreasing uric acid excretion Increasing accumulation of uric acid Inducing gout occur Initially penicillin was in critically short supply probenecid(丙磺舒) (a simple benzoic acid derivative was developed to block rapid excretion of penicillin) Today used as an uricosuric agent (also prevents uric acid reabsorption). for example : Streptomycin(链霉素) 0.5g Q6H High concentration in urine fluid . 100 time higher in urine than in blood . Treatment inflammation in uric tract. Sulfonamides in acid urine Concentration Crystallization GI tract excretion 肠肝循环(hepatoenteral circulation) liver blood bile gall bladder GI tract Hepatic Excretion Drugs can be excreted in bile, especially when the are conjugated with glucuronic acid Bile duct Intestines Portal vein Drug is absorbed glucuronidated or sulfatated in the liver and secreted through the bile glucuronic acid/sulfate is cleaved off by bacteria in GI tract drug is reabsorbed (example steroid hormones, contraceptives) latex The concentration of basic drugs are higher than acidic drugs in the latex. eg. morphine、Propylthiouracil(丙基硫氧嘧啶) Pulmonary excretion Sweat gland, lacriminal Part 3 basic concepts of pharmacokinetics Time-concentration curve Two kinds of elimination kinetics Compartment model Pharmacokinetics parameters Pharmacokinetics of single vs multiple dosing Two levels Three durations Three points •药物消除半衰期(Half-Life,t1/2) The time it takes for half of drug to be eliminated from the body. Give 1 2 3 4 5 6 100 mg of a drug half-life ………….. 50 half-lives………… 25 half-lives …….…..12.5 half-lives ………… 6.25 half-lives ………… 3.125 half-lives …………. 1.56 5 half-lives = 97% of drug eliminated 当仃止用药时间达到5个药物的t1/2时,药物的血浓度 (或体存量)仅余原来的3%,可认为已基本全部消除。 First order kinetics K为消除速率常数,是药动学中的一 项重要参数,它并不随时间而发生变化, 是药物本身固有的属性。 two-kinds of elimination kinetics First-order elimination kinetics More quickly drug in plasma eliminates from body, higher concentration of the drug is, so it called fixed percentage elimination. fixed half time. If the concentration’s unit is expressed by logarithm, the c-t curve is a beeline. Most of drugs used by clinical dosages are eliminated by first order kinetics. Zero order kinetics Characters of zero order kinetics •The eliminated rate has no relationship with the drug concentration. •The quantity of eliminated drugs in per unit of time are fixed. • Having no fixed half life. •If the concentration are expressed by numerical value, the Ct curve are a beeline. •When drugs in the body are excessive to exceed the maxim eliminative ability, the kinetics of the drug in the body is according to zero order kinetics; while the concentration descends to the range which the body can eliminate, the kinetics will accord to first order kinetics. Zero order First order Compartment model Pharmacokinetic model have no physiologic meaning, but can be described schematically or mathematically According to elimination rate constant(k) of drug in different tissue and organ。 房室模型 (compartment model) 房室模型 (compartment model) Apparent volume of distribution (表观分布容积) Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug in blood or plasma. ( L/kg, L ) Vd=Dosage/C(plasma) Volume of Distribution Plasma ~ 3 L Blood ~ 5 L Extracellular fluid ~18 L Total body water ~50-60 L confined to plasma distributed in body tissue Bioavailability(F):is defined as the fraction of the administered drug reaching the systemic circulation as intact drug. Bioavailabilty is highly dependent on both the route of administration and the drug formulation. 绝对生物利用度 口服等量药物AUC F= 静注等量药物AUC × 100% 相对生物利用度 F= 受试药AUC 标准药AUC × 100% The formulation of a drug also affects its absorption: BIOEQUIVALENCE Drugs may have the same bioavailability, but they may not be bioequivalent (= have the same pharmacological effect). BIOEQUIVALENCE AUC Formulation 1 = 100 mcg/ml/min AUC Formulation 2 = 100 mcg/ml/min BIOEQUIVALENCE Drugs with same bioavailability may not have the same bioequivalence. This normally is not as important as pharmaceutical companies state, but it can become an issue for drugs with a narrow therapeutic window. % Oral bioavailability = AUC (po) X 100 AUC (iv) = 50 mcg/ml/min X 100 100 mcg/ml/min = 50% Clearance Another “constant” that describes drug elimination = volume of plasma “cleared” of drug per unit time (mL/min) • 清除率(clearance,Cl) 单位时间内有多少分布容积中的药物被清除 (单位:ml/min or L/hr) 计算公式: Adjusting doses when clearance has changed because of disease or age Time-concentration curve of continuous administration drug Change of Css(稳态浓度) Drug concentration of steady state in blood Dosing rate equals rate of elimination after 4-5t½ drug concentration relatively exhibits steady level (concentration,Css), also it was called as plateau(坪值) Dosing rate =Rate of elimination (If same intermittent doses are given) CSS max: maximum concentration of steady state( Peak C) Css min: minimum concentration of steady state Peak Time: It is a time achieving the CSS max Relationship between dosing rate and drug concentration in steady state Ass: amount of drug in the body Css: concentration in steady state R: dosing rate Continuous repeating administration in intravenous injection Administration dose: D Dosing interval: τ In steady state: dosing rate=rate of elimination R=Ass·k Ass=Css·Vd R=D/τ = Css·Vd·k = Css·Vd·0.693/t1/2 Css=1.44·t1/2D/(Vd·τ ) Ass=1.44·t1/2D/τ Css=1.44·t1/2D/(Vd·τ ) Changing dosing interval 0.5t1/2, t1/2,2t1/2, ;no changing dosage D, Css change, while tss not Css=1.44·t1/2D/(Vd·τ ) Changing dosage 2D, D, 0.5D; no changing interval t1/2, Css change , while tss not Loading dose It is a first dosing amount that achieves Css rapidly, before given routine dose Loading dose=Amount in the body achieving Css immediately following the loading dose Loading dose is a beginning dose that promptly raises the concentration of drug in plasma to the target concentration Generally speaking: Oral administration: dosing interval is t1/2 or so Loading dose=Two times the amount of routine administration dose =Administrated dosage·2