国我私特 ©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 2013.3 the GIT. chenjian@situ.edu.cn 国生一 Terms 国人烧 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 2013.3 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 国生 Pathways of drug absorption 国Passive diffusion Along the concentration gradient 主动转运 No specific carrier proteins involved ·No energy usage 饱和点 Absorption type of most drugs 破动扩散 药张以一 皮 Pathways of drug absorption 国一 Anatomical structure of GIT ©Passive diffusion ·Fick's first law of diffusion菲克第一扩散定律 (do） (Cx-C dt g =DAwRa/g△Xe SALIVARY GLANDS- -PHARYNX (dQ/dt)the rate of the quantity Q entering the bloodstream D the diffusion coefficient of the drug through the membrane ESOPHAGUS A the surface area of the absorbing membrane available for drug diffusion R the partition coefficient of the drug between the membrane and aqueous LIVER GALLBLADDER STOMACH gut fluids (c-c)the concentrate gradient across the membrane LARGE SMALL INTESTINE AX the thickness of the membrane ®(dQdt)。b=KC. Pathways of drug absorption 国秋生 Stomach Active transport The primary functions of stomach are storage, Works against a concentration mixing,and reducing all components to a slurry gradient with the aid of gastric secretions;and then Requires a specific carrier protein emptying these contents in a controlled manner and cnergy Carrior loads Abaorption type of glucose,amino 0us8ca into the upper small intestine. acids.k'Na and some vitamins The surface tension of gastric fluid is low. The pH of gastric fluid is 1~3.5 and then 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 Shanghai Jiao Tong University Anatomical structure of GIT 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
国生 Small Intestine 国生 国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 国Pancreas胰脏 ·Juice:bicarbonates and en☑ymes .Bicarbonate secretion is capable of maintaining a neutral pH 国生一 Small Intestine 国话生一 Large Intestine ④Three 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 国生一 Small Intestine 国生 Process of drug absorption For its primary role of digestion and absorption,the me small intestine has a unique surface structure by ① which it greatly increases its effective luminal d MMm surface area. MMM ·Folds 皱襞 ·Villi 绒毛 ·Microvilli微绒毛 3
3 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 Shanghai Jiao Tong University Process of drug absorption
圈生一Process of drug absorption 国生 Physicochemical factors-Dissolution ©Diffusion model ®Introduction Nernst-Brunner equation .Getting the drug into its site of absorption dQ .Getting the drug into solution:factors affecting the rate of dissolution =DAC:-Cp) 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 国线一 国生Physicochemical factors-Dissolution ©Diffusion model Factors influencing drug absorption and drug Nernst-Brunner equation Q-DAC,-C) availability .Noyes-Whitney equation .Physicochemical factors 市=&G-) 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 国线一 国生 Physicochemical factors-Dissolution Nernst-Brunner equation Physicochemical factors 4Q-DAC.-C) ·Dissolution溶出 ·Oil/water partition coefficient(油水分配系数) Effective surface area of the drug ·pKa .Saturation solubility of the drug ·Molecular weight Drug concentration in bulk solution ·Diffusion coefficient .Thickness of the stationary diffusion layer 4
4 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 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
④t生Physicochemical factors-Dissolution 国生 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 国丛生 Physicochemical factors-Dissolution 国话生Physicochemical factors-Kow Saturation Solubility of the Drug ©Oil/Water Partition Coefficients(Kow） ·Salt form of the drug ·pH effect 图KONF Drug concentration in oil phase ·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 dQ dt Da 圈生一 Physicochemical factors-Dissolution 圈屹Physicochemical factors-Kow Drug concentration in bulk solution Nernst-Brunner equation It is generally believed that drug molecules must be 4Q-DAC-C) lipophilic to have good absorption because drug molecules must penetrate the lipid bilayer of most ·Sink condition漏悟条件 cellular membranes. ·Assumption:Cb<Cs Compound with extremely high lipophilicity would be unable to enter the aqueous cytosolic domain,and If a drug is absorbed through the GI membrane very slowly,drug concentration in the GIT fluids may build so would be unable to exit from the lipophilic up.This buildup would,by decreasing the gradient. membrane. decrease the dissolution rate. 5
5 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: 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