国特 u✉ ©i生Introduction and concept Drugs are most often introduced into the body by the oral route of administration. ORAL ABSORPTION Drug absorption is the penetration of the drug School of Pharmacy across the intestinal "membrane"and its Chen Jian appearance,unchanged in the blood draining 2011.2 the GIT. chenjian@situ.edu.cn 国生一 Terms 国生 Pathways of drug absorption 国GlT:gastrointestinal tract胃肠道 ©Bioavailability生物利用度 ©Drug concentration--time curve药时曲线 ®AUC:area under the curve曲线下面积 国Cmax达峰值 国Tma达峰时 ④Fluid mosaic modeli流动镶嵌模型 The basic structure of the membrane is lipid bilayer. .There are proteins on or in the membrane. The membrane is semipermeable. 圈生一 Oral absorption 国tt线Pathways of drug absorption Introduction and concept of absorption Drugs are absorbed in different ways across the epithelial Anatomical and physiological consideration of boundary between the GIT and the bloodstream GIT ·Endocytosis内吞 Factors influencing drug absorption and drug availability ·Paracellular Diffusion(Pore transport膜孔转运) Physicochemical factors ·Passive diffusion被动扩散 Physiological factors ·Active transport主动转运 ·Other factors ·Facilitated diffusion促进转运 1
1 ORAL ABSORPTION School of Pharmacy Chen Jian 2011.2 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Terms GIT: gastrointestinal tract胃肠道 Bioavailability 生物利用度 Drug concentration-time curve药时曲线 AUC: area under the curve曲线下面积 Cmax达峰值 Tmax达峰时 Shanghai Jiao Tong University Oral absorption Introduction and concept of absorption Anatomical and physiological consideration of GIT Factors influencing drug absorption and drug availability • Physicochemical factors • Physiological factors • Other factors Shanghai Jiao Tong University Introduction and concept Drugs are most often introduced into the body by the oral route of administration. Drug absorption is the penetration of the drug across the intestinal “membrane” and its appearance, unchanged in the blood draining the GIT. Shanghai Jiao Tong University Pathways of drug absorption Fluid mosaic model流动镶嵌模型 • The basic structure of the membrane is lipid bilayer. • There are proteins on or in the membrane. • The membrane is semipermeable. Shanghai Jiao Tong University Pathways of drug absorption Drugs are absorbed in different ways across the epithelial boundary between the GIT and the bloodstream • Endocytosis内吞 • Paracellular Diffusion (Pore transport膜孔转运) • Passive diffusion被动扩散 • Active transport主动转运 • Facilitated diffusion促进转运
圈上生一 Pathways of drug absorption ©生Pathways of drug absorption 国Passive diffusion ©Active transport Along the concentration gradient peptide transporters(B-lactam antibiotics) No specific carrier proteins involved nucleoside transporters ·No energy usage Absorption type of most drugs ·sugar transporters bile acid transporters amino acid transporters organic anion transporters 。… Pathways of drug absorption Pathways of drug absorption ©Passive diffusion ·Fick's first law of diffusion菲克第一扩散定律 动转运 (do） (Cx-C dt g =DAw'R/m△XE (dodt)the rate of the quantity entering the bloodstream 饱和点 D the diffusion coefficient of the drug through the membrane A the surface area of the absorbing membrane available for drug diffusion 破动扩散 R the partition coefficient of the drug between the membrane and aqueous gut fluids (c-c)the concentrate gradient across the membrane 药特张度 AX the thickness of the membrane ®(dQdt)。b=KC. 圈上生一 Pathways of drug absorption Anatomical structure of GIT ®Active transport Works against a concentration gradient SALIVARY GLANDS PHARYNX Requires a specific carrier protein and energy Carrior loads ESOPHAGUS Abaorption type of glucose,amino 0us8ca acids.k'Na and some vitamins LIVER GALLBLADDER tramsverse coloe ASREA LARGE acending colou Kjunum SMALL INTESTINE and then inside of cel 2
2 Shanghai Jiao Tong University Passive diffusion • Along the concentration gradient • No specific carrier proteins involved • No energy usage • Absorption type of most drugs Pathways of drug absorption Shanghai Jiao Tong University Passive diffusion • Fick’s first law of diffusion 菲克第一扩散定律 (dQ/dt) g→b the rate of the quantity Q entering the bloodstream Dm the diffusion coefficient of the drug through the membrane Am the surface area of the absorbing membrane available for drug diffusion Rm/aq the partition coefficient of the drug between the membrane and aqueous gut fluids (cg-cb) the concentrate gradient across the membrane ∆Xm the thickness of the membrane (dQ/dt) g→b =KCg Pathways of drug absorption Shanghai Jiao Tong University Pathways of drug absorption Active transport • Works against a concentration gradient • Requires a specific carrier protein and energy • Absorption type of glucose, amino acids, k+,Na+ and some vitamins Shanghai Jiao Tong University Pathways of drug absorption Active transport • peptide transporters (β-lactam antibiotics) • nucleoside transporters • sugar transporters • bile acid transporters • amino acid transporters • organic anion transporters • …. Shanghai Jiao Tong University Pathways of drug absorption Shanghai Jiao Tong University Anatomical structure of GIT
国生一 Stomach 国生一 Small Intestine The primary functions of stomach are storage, For its primary role of digestion and absorption,the mixing,and reducing all components to a slurry small intestine has a unique surface structure by with the aid of gastric secretions;and then which it greatly increases its effective luminal emptying these contents in a controlled manner surface area. into the upper small intestine. ·Folds 皱装 The surface tension of gastric fluid is low. The pH of gastric fluid is 1~3.5 ·Villi 绒毛 ·Microvilli微绒毛 国生 Small Intestine 国线一 ©Gallbladder胆囊 Bile produced by the liver Small intestine is the main site of Bile salts are surfactant drug absorption. Bile salts responsible for micelle formation and subsequent solubilization of monoglycerides and fatty ·Large surface area acids,allowing them to penetrate the intestinal mucosa. Highly perfused with capillaries @Pancreas胰脏 Juice:bicarbonates and enzymes .Bicarbonate secretion is capable of maintaining a neutral pH 国生 Small Intestine 国秋生 Large Intestine Three sections The large intestine has two primary functions:the absorption of water and electrolytes,and the storage ·Duodenum十二指肠30cm and elimination of fecal material.It is not the main ·Jejunum空肠240cm site of drug absorption because of its limited surface area. ·leum回肠360cm ·Cecum盲肠 ·Colon结肠 ·Rectum直肠 3
3 Shanghai Jiao Tong University Stomach The primary functions of stomach are storage, mixing, and reducing all components to a slurry with the aid of gastric secretions; and then emptying these contents in a controlled manner into the upper small intestine. The surface tension of gastric fluid is low. The pH of gastric fluid is 1~3.5 Shanghai Jiao Tong University Small Intestine Gallbladder胆囊 • Bile produced by the liver • Bile salts are surfactant • Bile salts responsible for micelle formation and subsequent solubilization of monoglycerides and fatty acids, allowing them to penetrate the intestinal mucosa. Pancreas胰脏 • Juice: bicarbonates and enzymes • Bicarbonate secretion is capable of maintaining a neutral pH Shanghai Jiao Tong University Small Intestine Three sections • Duodenum十二指肠 30cm • Jejunum 空肠240cm • Ileum 回肠360cm Shanghai Jiao Tong University Small Intestine For its primary role of digestion and absorption, the small intestine has a unique surface structure by which it greatly increases its effective luminal surface area. • Folds 皱襞 • Villi 绒毛 • Microvilli 微绒毛 Shanghai Jiao Tong University Small intestine is the main site of drug absorption. • Large surface area • Highly perfused with capillaries Shanghai Jiao Tong University Large Intestine The large intestine has two primary functions: the absorption of water and electrolytes, and the storage and elimination of fecal material. It is not the main site of drug absorption because of its limited surface area. • Cecum盲肠 • Colon结肠 • Rectum直肠
圈达生一 Process of drug absorption 国生 ① Physicochemical factors AMm ·Dissolution溶出 ·Oil/water partition coefficient(油水分配系数) ·pKa ·Molecular weight 地 国ft线Process of drug absorption 国生 Physicochemical factors-Dissolution ©Diffusion model ®Introduction Nernst-Brunner equation .Getting the drug into its site of absorption .Getting the drug into solution:factors affecting the rate of dissolution =DAC.-Co) dt h Gastrointestinal membrane transport D=diffusion coefficient of the drug Moving the drug away from the site of absorption A=effective surface area of the drug particles The slowest of the four steps will determine the rate of h=thickness of a stationary layer of solvent availability of the drug from an oral dosage form. Cs=saturation solubility of the drug C=concentration of drug in the bulk fluids 国生一 Physicochemical factors-Dissolution ④Diffusion model Factors influencing drug absorption and drug Nernst-Brunner equation Q-DA C,-C) availability Noyes-Whitney equation Physicochemical factors dt=(G-C) K三 D Physiological factors S:surface area of drug exposed to the dissolution media ·Other factors .D:diffusion coefficient .V:volume of the dissolution media h thickness of a stationary layer of solvent 4
4 Shanghai Jiao Tong University Process of drug absorption Shanghai Jiao Tong University Process of drug absorption Introduction • Getting the drug into its site of absorption • Getting the drug into solution: factors affecting the rate of dissolution • Gastrointestinal membrane transport • Moving the drug away from the site of absorption The slowest of the four steps will determine the rate of availability of the drug from an oral dosage form. Shanghai Jiao Tong University Factors influencing drug absorption and drug availability • Physicochemical factors • Physiological factors • Other factors Shanghai Jiao Tong University Physicochemical factors • Dissolution 溶出 • Oil/water partition coefficient(油水分配系数) • pKa • Molecular weight Shanghai Jiao Tong University Physicochemical factors-Dissolution Diffusion model • Nernst-Brunner equation D=diffusion coefficient of the drug A=effective surface area of the drug particles h=thickness of a stationary layer of solvent CS=saturation solubility of the drug Cb =concentration of drug in the bulk fluids Shanghai Jiao Tong University Physicochemical factors-Dissolution Diffusion model • Nernst-Brunner equation • Noyes-Whitney equation • S: surface area of drug exposed to the dissolution media • D: diffusion coefficient • V: volume of the dissolution media • h: thickness of a stationary layer of solvent KS(C C ) dt dC S Vh D K
圈上攻达线 Physicochemical factors-Dissolution 圈生一 Physicochemical factors-Dissolution Drug concentration in bulk solution Nernst-Brunner equation Nernst-Brunner equation 4Q=DA C-Cx) 4Q-DAC-C2 故 h .Effective surface area of the drug ·Sink condition漏槽条件 ·Assumption:Cb<<Cs Saturation solubility of the drug Drug concentration in bulk solution If a drug is absorbed through the GI membrane very slowly,drug concentration in the GIT fluids may build Diffursion coefficient up.This buildup would,by decreasing the gradient, decrease the dissolution rate. Thickness of the stationary diffusion layer 圈线_Physicochemical factors--Dissolution 国线一 Effective surface area of the drug Physicochemical factors ·Dissolution ·Particle size Oil/water partition coefficient ·pKa Disintegration and deaggregation ·Molecular weight Effect of manufacturing processes Physicochemical factors-Dissolution 圈屹Physicochemical factors-Kow Saturation Solubility of the Drug Oil/Water Partition Coefficients(Ko) ·Salt form of the drug Drug concentration in oil phase ·pH effect ©KowF ·Solvate formation溶剂化物 Drug concentration in water phase ·Polymorphism多晶型 Fick's first law of diffusion: ·Complexation Solid-solid interaction d dt 5
5 Shanghai Jiao Tong University Nernst-Brunner equation • Effective surface area of the drug • Saturation solubility of the drug • Drug concentration in bulk solution • Diffusion coefficient • Thickness of the stationary diffusion layer Physicochemical factors-Dissolution Shanghai Jiao Tong University Physicochemical factors-Dissolution Effective surface area of the drug • Particle size • Disintegration and deaggregation • Effect of manufacturing processes Shanghai Jiao Tong University Physicochemical factors-Dissolution Saturation Solubility of the Drug • Salt form of the drug • pH effect • Solvate formation溶剂化物 • Polymorphism 多晶型 • Complexation • Solid-solid interaction Shanghai Jiao Tong University Physicochemical factors-Dissolution Drug concentration in bulk solution • Nernst-Brunner equation • Sink condition漏槽条件 • Assumption: Cb<<CS • If a drug is absorbed through the GI membrane very slowly, drug concentration in the GIT fluids may build up. This buildup would, by decreasing the gradient, decrease the dissolution rate. Shanghai Jiao Tong University Physicochemical factors • Dissolution • Oil/water partition coefficient • pKa • Molecular weight Shanghai Jiao Tong University Drug concentration in oil phase KO/W= Drug concentration in water phase Physicochemical factors-KO/W Oil/Water Partition Coefficients (KO/W) Fick’s first law of diffusion:
圈上生一Physicochemical factors--Kow 圈生一 Physicochemical factors-pK It is generally believed that drug molecules must be 图plH-partition hypothesis pH分配假说 lipophilic to have good absorption because drug molecules must penetrate the lipid bilayer of most lonizable compounds penetrate biological membranes cellular membranes. primarily in the nonionized form.As a result,acidic Compound with extremely high lipophilicity would drugs should best be absorbed from acidic solutions for be unable to enter the aqueous cytosolic domain,and which pH <pK,whereas basic compounds would best so would be unable to exit from the lipophilic be absorbed from alkaline solutions for which pH membrane. 国生一 国线一 Physicochemical factors-pK Physicochemical factors Most drugs,whether ionized or nonionized(i.e., regardless of pH),are best absorbed from the small ·Dissolution intestine as a result of the large absorbing surface Oil/water partition coefficient area of this region. ·pKa ·Molecular weight 圈生一 Physicochemical factors-pK 国秋生 Most drug molecules are either weak acids or bases Physicochemical factors that will ionized to an extent determined by the compound's pKa and the pH of the biological fluid ·Dissolution in which it is dissolved. Oil/water partition coefficient The importance of ionization in drug absorption is ·pKa based on the observation that the nonionized form of ·Molecular weight the drug has a greater Kow. 6
6 Shanghai Jiao Tong University Physicochemical factors-KO/W It is generally believed that drug molecules must be lipophilic to have good absorption because drug molecules must penetrate the lipid bilayer of most cellular membranes. Compound with extremely high lipophilicity would be unable to enter the aqueous cytosolic domain, and so would be unable to exit from the lipophilic membrane. Shanghai Jiao Tong University Physicochemical factors • Dissolution • Oil/water partition coefficient • pKa • Molecular weight Shanghai Jiao Tong University Physicochemical factors-pKa Most drug molecules are either weak acids or bases that will ionized to an extent determined by the compound’s pKa and the pH of the biological fluid in which it is dissolved. The importance of ionization in drug absorption is based on the observation that the nonionized form of the drug has a greater Ko/w. Shanghai Jiao Tong University Physicochemical factors-pKa pH-partition hypothesis pH分配假说 • Ionizable compounds penetrate biological membranes primarily in the nonionized form. As a result, acidic drugs should best be absorbed from acidic solutions for which pH ＜pKa, whereas basic compounds would best be absorbed from alkaline solutions for which pH＞ pKa. Shanghai Jiao Tong University Physicochemical factors-pKa Most drugs, whether ionized or nonionized (i.e., regardless of pH), are best absorbed from the small intestine as a result of the large absorbing surface area of this region. Shanghai Jiao Tong University Physicochemical factors • Dissolution • Oil/water partition coefficient • pKa • Molecular weight
圈上生一 Physicochemical factors-MW Physiological factors-GI fluids Various materials,particularly bile salts,enzymes,and mucin, Passive absorption in the gastrointestinal tract is influence absorption. severely limited by the size of the penetrating drug Bile salts,which are highly surfacective,may enhance the rate or molecule. extent of absorpton of poorly drugs by increasing the rate of dissolution in the Gl fuids. The optimal molecular weight is less than 500. Bile salts may also reduce drug absorption through the formation of water-insoluble,nonabsorbable complex. Some enrymes may act with some drugs. intestinal epithelium,has been thought to bind certain drugs 国生一 Physiological factors 国生 Physiological factors Components and properties of GI fluids. Components and properties of GI fluids. 国Gastric emptying胃排空 ④Gastric emptying ⊕Intestinal transit Intestinal transit Blood flow ©Blood flow 圈t笔Physiological factors-GIfluids 国生Physiological factors-Gastric emptying pH value of Gl fluids varies considerably along GIT. .The gastric fluids are highly acidic,usually ranging from pH Ito Gastric emptying influences the rate(and possibly the 3.5. extent)of absorption because it determines the .The pH of intestinal fluids gradually increases when moving in movement of drug from the stomach to the small the distal direction,ranging from approximately 5.7to7.7. intestine which is the best absorptive site for most drugs. .The fluids in the large intestine are generally considered to have Gastric emptying pattems are distinctly different, a pH of between 7 and 8. depending on the absence or presence of food. GI fluids pH would influence the drug solubility, permeability,and stability. 7
7 Shanghai Jiao Tong University Physicochemical factors-MW Passive absorption in the gastrointestinal tract is severely limited by the size of the penetrating drug molecule. The optimal molecular weight is less than 500. Shanghai Jiao Tong University Physiological factors Components and properties of GI fluids. Gastric emptying胃排空 Intestinal transit Blood flow Shanghai Jiao Tong University Physiological factors-GI fluids pH value of GI fluids varies considerably along GIT. • The gastric fluids are highly acidic, usually ranging from pH 1 to 3.5. • The pH of intestinal fluids gradually increases when moving in the distal direction, ranging from approximately 5.7 to 7.7. • The fluids in the large intestine are generally considered to have a pH of between 7 and 8. GI fluids pH would influence the drug solubility, permeability, and stability. Shanghai Jiao Tong University Physiological factors-GI fluids Various materials, particularly bile salts, enzymes, and mucin, influence absorption. • Bile salts, which are highly surface-active, may enhance the rate or extent of absorption of poorly water-soluble drugs by increasing the rate of dissolution in the GI fluids. • Bile salts may also reduce drug absorption through the formation of water-insoluble, nonabsorbable complex. • Some enzymes may act with some drugs. • Mucin, a viscous mucopolysaccharide that lines and protects and the intestinal epithelium, has been thought to bind certain drugs nonspecifically, prevent or reduce absorption. Shanghai Jiao Tong University Physiological factors Components and properties of GI fluids. Gastric emptying Intestinal transit Blood flow Shanghai Jiao Tong University Physiological factors-Gastric emptying Gastric emptying influences the rate (and possibly the extent) of absorption because it determines the movement of drug from the stomach to the small intestine which is the best absorptive site for most drugs. Gastric emptying patterns are distinctly different, depending on the absence or presence of food
圈>f线一Gastric mtying-inthe absence offd ©i生Physio factors-Gastric emptying In the absence of food,the empty stomach and the intestinal tract undergo a sequence of repetitious events referred to as the interdigestive migrating The factors affecting stomach emptying notor complex(消化间期移行性复合运动)which is Food composed of four stages at a period of 2 hours. 国Drug Stage 1:minimal activity,about Ih. Stage 2:irregular contractions that gradually increase in ©Sickness strength,30-45 min. ©Others Stage 3:intense peristaltic waves that result in the emptying ·Body position of gastric contents,5-15 min.(housekeeper waves) ·Viscosity Stage 4:a transition of decreasing activity,leading to the beginning of the next cycle. .Emotional state...... 国ft线Gastric emptying--in the absenceoffood 国生 Gastric emptying The gastric residence time of a solid dosage form will An increased gastric-emptying rate will vary from perhaps 5 to 15 minutes if ingested at the probably increase the rate of absorption for beginning of the housekeeper to about 2 hours or longer if drugs absorbed by passive diffusion. ingested at the end of the housekeeper. An increased gastric-emptying rate will The foregoing considerations will not apply to liquid probably decrease the extent of absorption for dosage forms which are generally able to empty during all phases of the migrating motor complex. drugs absorbed by active transport. ©上t线_Gastric emptying-ithe presenceof food 国秋生 Physiological factors Components and properties of GI fluids. In the presence of food,gastric emptying is ©Gastric emptying controlled by a complex variety of mechanical, ©Intestinal transit hormonal,and neural mechanisms. ©Blood flow 8
8 Shanghai Jiao Tong University Gastric emptying-in the absence of food In the absence of food, the empty stomach and the intestinal tract undergo a sequence of repetitious events referred to as the interdigestive migrating motor complex(消化间期移行性复合运动) which is composed of four stages at a period of 2 hours. • Stage 1: minimal activity, about 1h. • Stage 2: irregular contractions that gradually increase in strength, 30-45 min. • Stage 3: intense peristaltic waves that result in the emptying of gastric contents, 5-15 min. (housekeeper waves) • Stage 4: a transition of decreasing activity, leading to the beginning of the next cycle. Shanghai Jiao Tong University Gastric emptying-in the absence of food The gastric residence time of a solid dosage form will vary from perhaps 5 to 15 minutes if ingested at the beginning of the housekeeper to about 2 hours or longer if ingested at the end of the housekeeper. The foregoing considerations will not apply to liquid dosage forms which are generally able to empty during all phases of the migrating motor complex. Shanghai Jiao Tong University Gastric emptying-in the presence of food In the presence of food, gastric emptying is controlled by a complex variety of mechanical, hormonal, and neural mechanisms. Shanghai Jiao Tong University Physiological factors-Gastric emptying The factors affecting stomach emptying Food Drug Sickness Others • Body position • Viscosity • Emotional state…… Shanghai Jiao Tong University Gastric emptying An increased gastric-emptying rate will probably increase the rate of absorption for drugs absorbed by passive diffusion. An increased gastric-emptying rate will probably decrease the extent of absorption for drugs absorbed by active transport. Shanghai Jiao Tong University Physiological factors Components and properties of GI fluids. Gastric emptying Intestinal transit Blood flow
Physiological factors-Intestine transit Physiological factors-Intestine transit The longer the residence time in the small intestine,the greater the potential for complete absorption. Rectum Once emptied from the stomach,material will move along ®Small surface area the small intestine and reach the ileocecal valve in about 3 ©Little fluid content hours. ®Poor mixing The short time in small intestine is critical to the For infants and children performance of poorly water-soluble drugs,slowly Absorption is effected by fecal material and dissolving,coated dosage forms(enteric or polymer coated). retention time and sustained-release forms. Physiological factors-Intestine transit 国生 Physiological factors Ingest drugs before a meal Components and properties of GI fluids. Avoid problems associated with gastric ©Gastric emptying emptying Intestinal transit .Reduce potential drug interactions with food ©Blood f1ow components Avoid the more viscous environment in the gut Physiological factors-Intestine transit Physiological factors-Blood flow Colon Much longer residence time As a result of rapid blood perfusion of the GIT, ®mild pH the blood at the site of absorption represents a Low enzymatic activity virtual sink for absorbed material ©Small surface area Relative viscous fluidlike environment Usually,blood flow is not an important Large colonies of bacteria consideration in drug absorption. 9
9 Shanghai Jiao Tong University Physiological factors-Intestine transit The longer the residence time in the small intestine, the greater the potential for complete absorption. Once emptied from the stomach, material will move along the small intestine and reach the ileocecal valve in about 3 hours. The short time in small intestine is critical to the performance of poorly water-soluble drugs, slowly dissolving, coated dosage forms (enteric or polymer coated), and sustained-release forms. Shanghai Jiao Tong University Physiological factors-Intestine transit Ingest drugs before a meal • Avoid problems associated with gastric emptying • Reduce potential drug interactions with food components • Avoid the more viscous environment in the gut Shanghai Jiao Tong University Physiological factors-Intestine transit Colon Much longer residence time mild pH Low enzymatic activity Small surface area Relative viscous fluidlike environment Large colonies of bacteria Shanghai Jiao Tong University Physiological factors-Intestine transit Rectum Small surface area Little fluid content Poor mixing For infants and children Absorption is effected by fecal material and retention time Shanghai Jiao Tong University Physiological factors Components and properties of GI fluids. Gastric emptying Intestinal transit Blood flow Shanghai Jiao Tong University Physiological factors-Blood flow As a result of rapid blood perfusion of the GIT, the blood at the site of absorption represents a virtual sink for absorbed material. Usually, blood flow is not an important consideration in drug absorption
国生一 Other factors 圈生一 Other factors-Metabolism ©Metabolism ④Other factors ·Frst-pass effect首过效应：An absorbed drug will first go to the liver,which is the primary site of drug metabolism in the body, Drug-food and drug-drug interactions the drug may be metabolized extensively before systemic ·Metabolism distribution. First-pass effect refers to all processes of metabolism before the ·Disease states drug reaches the systemic circulation,which take place primarily in the gut and liver. ·Age 国生 Other factors 国话生一 Other factors Drug-food and drug-drug interactions Drug absorption is generally less efficient when food present in Disease states:Gastrointestinal disorders and disease the GIT,although there are several exceptions. states are likely to influence drug absorption. .1.delay in gastric emptying. Age:pediatric and geriatric population .2.stimulation of bile flow, 3.a change in the pH of the Gl tract; .4.an increase in splanchnic blood flow; .5.a change in luminal metabolism of the drug substance; .6.physical or chemical interaction of the meal with the drug product or drug substance. 国生一 Other factors 国话线Absorption-Leaming objectives ©Metabolism Metabolism by enzymes Concept ofabsorption Acid-or base-mediated drug breakdown Mechanism of absorption Anatomical structure of GIT Variables which affect absorption Diffusion model/Nernst-Bruner equation Fluid mosaic model/Fick's first law Blood flow/First-pass effect ®Sink condition 10
10 Shanghai Jiao Tong University Other factors Other factors • Drug-food and drug-drug interactions • Metabolism • Disease states • Age Shanghai Jiao Tong University Other factors Drug-food and drug-drug interactions • Drug absorption is generally less efficient when food present in the GIT, although there are several exceptions. • 1. delay in gastric emptying; • 2. stimulation of bile flow; • 3. a change in the pH of the GI tract; • 4. an increase in splanchnic blood flow; • 5. a change in luminal metabolism of the drug substance; • 6. physical or chemical interaction of the meal with the drug product or drug substance. Shanghai Jiao Tong University Other factors Metabolism • Metabolism by enzymes • Acid- or base-mediated drug breakdown Shanghai Jiao Tong University Other factors-Metabolism Metabolism • First-pass effect首过效应: An absorbed drug will first go to the liver, which is the primary site of drug metabolism in the body; the drug may be metabolized extensively before systemic distribution. • First-pass effect refers to all processes of metabolism before the drug reaches the systemic circulation, which take place primarily in the gut and liver. Shanghai Jiao Tong University Other factors Disease states: Gastrointestinal disorders and disease states are likely to influence drug absorption. Age: pediatric and geriatric population Shanghai Jiao Tong University Absorption- Learning objectives Concept of absorption Mechanism of absorption Anatomical structure of GIT Variables which affect absorption Diffusion model/Nernst-Bruner equation Fluid mosaic model/Fick’s first law Blood flow/First-pass effect Sink condition