FACTORS EFFECTING ABSORPTION OF DRUG

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ANATOMICAL AND PHYSIOLOGICAL factors affecting DRUG ABSORPTION:

ANATOMICAL AND PHYSIOLOGICAL factors affecting DRUG ABSORPTION BY R.NAVEEN KUMAR M.PHARM ACY PHARMACEUTICAAL TECHNOLOGY SRINIVASA RAO COLLEGE OF PHARMACY VISAKHAPATNAM-41 ANDHRA PRADESH 1 Under the guidance of Dr. R.Santosh Kumar M.Pharm.,Ph.D

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Contents INTRODUCTION DRUG ABSORPTION SCHEMATIC EVENT DURING ABSORPTION FACTORS EFFECTING ABSORPTION PHYSICOCHEMICAL FACTORS PHARMACEUTICAL FACTORS PHYSICALTY FACTORS GASTROINTESTINAL TRACT ANATOMICAL FACTORS PHYSIOLOGICAL AND PATHOLOHICAL FACTORS 2

Introduction :

Introduction Absorption process is developed in the biological system for getting required organi c and inorganic chemicals(nutrients) into the systemic circulation to maintain life . Similar process adopted for absorption of drugs. As majority of drugs are orally administered are intended to be absorbed from the GIT 3

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ABSORPTION OF DRUGS :

ABSORPTION OF DRUGS What is drug absorption? It is defined as the process of movement of unchanged drug from the site of administration to the systemic circulation . 5

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As the effectiveness of drug can only be assessed from plasma. There always exist a correlation between the plasma concentration of a drug & the therapeutic response Thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement . i.e., plasma. 6

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Minimum effective conc. Therapeutic success of a rapidly & completely absorbed drug. Therapeutic failure of a slowly absorbed drug. Subtherapeutic level Time Plasma Drug Conc . 7 PLOT SHOWING SIGNIFICANCE OF RATE AND EXTENT OF IN DRUG ABSORPTION a b

Systemic events during administration to absorption of drug :

Systemic events during administration to absorption of drug DISINTEGRATION DEAGGREGATION DISSOLUTION DRUG AT ABSORPTION SITE NON- IONIC IONIC GI lumen Blood 8

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SOLID DRUG DRUG AT ABSORPTION SITE DRUG IN SYSTEMIC CIRCULATION ABSORPTION DISSOLUTION 9

fACTORS INFLENCING GI ABSORPTION OF A DRUG FROM ITS DOSAGE FORM:

fACTORS INFLENCING GI ABSORPTION OF A DRUG FROM ITS DOSAGE FORM Physicochemical factors : which affects due to the “ Physicochemical properties of drugs .” 1 ) Drug solubility & dissolution rate 2) Particle size & effective surface area 3) Polymorphism & amorphism 4) Pseudo polymorphism ( hydrates/solvates) 10

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5) Salt form of the drug . 6) Lipophillicity of the drug pH-partition hypothesis . 7) pKa of drug & gastrointestinal pH . 8) Drug stability 9) Stereochemical nature of the drug 11

Pharmaceutical factors :

Pharmaceutical factors w hich affects due to the Dosage form characteristics & pharmaceutical ingredients 1) Disintegration time ( tablets/capsules) 2) Dissolution time 3) Manufacturing variables 4)Pharmaceutical excipients / adjuvants 5) Nature & type of dosage form 6) Product age & storage condition 12

Physicality factors :

Physicality factors Which Affects due to “ anatomical , physiological & pathological characteristics of patient.” 1) Age 2) Gastric emptying time 3) Intestinal transit time 4) Gastrointestinal pH. 5) Disease states 13

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6) Blood flow through the GIT 7) Gastrointestinal contents: a) Other drugs b) Food c) Fluids d) Other normal GI contents 8) Pre systemic metabolism by: a) Luminal enzymes b) Gut wall enzymes c) Bacterial enzymes d) Hepatic enzymes 14

Anatomical factors :

Anatomical factors 15

Gastrointestinal tract:

Gastrointestinal tract GIT comprises of number of compartments ,there primary function is Secretion Digestion Absorption. The mean length of GIT is 450cm. 16

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The major functional components of the GIT are stomach small intestine(duodenum, jejunum , ileum) large intestine ( colon) These grossly differ from each other in terms of anatomy, function , secretions , p H 17

Stomach :

Stomach The stomach is a bag like structure having smooth mucosa and thus small surface area . 18

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The surface area for absorption of drugs is relatively small in the stomach due to the absence of macrovilli & microvilli. The stomach is not principal region for drug absorption because: 1.) The total mucosal region is small 2.) More secreting cells than absorptive cells . 3.) Gastric residence time is limited 19

Small Intestine :

Small Intestine The small intestine , comprising of duodenum, jejunum and ileum has a unique surface structure making it ideally for digestion and absorption. All types of drugs are predominantly absorbed through the small intestine, The transit time of a dosage form is the major determinant of extent of absorption. 20

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It is a major site for absorption of most drugs due to its characteristics: 1 .)large surface area : Due to folds in intestinal mucosa kerckings result In 3 fold increase of surface area. 21

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Surface of folds posses finger like projections called as villi . Increases surface area 30times. The surface of villi protrudes several microvilli Increases surface area 600 times 22

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2.)Great length of small intestine: It is more than 200 square meters . 3.)Greater Blood Flow: The blood flow to small intestine is 6 to 10 times that of stomach. 4.)Favorable p H range : pH range is 5 to 7.5 favourable for drugs to remain unionised. 5.) Slow Peristaltic Movement: Prolongs the residence time of drug in intestine. 23

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6.)High permeability : The intestinal epithelium is dominated by absorptive cells. 24

Duodenum :

Duodenum The duodenum, into which the stomach opens, is about 25 cm long, C-shaped and begins at the pyloric sphincter . 25 Duodenum

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A common duct from the pancreas and the gallbladder enters into the duodenum. The duodenal pH is about 6 to 6.5 . Because of the presence of bicarbonate that neutralizes the acidic chyme emptied from the stomach . The pH is optimum for enzymatic digestion of protein and peptide food. 26

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Pancreatic juice containing enzymes is secreted into the duodenum from the bile duct. Trypsin, chymotrypsin, and carboxy peptidase are involved in the hydrolysis of proteins into amino acids . Amylase is involved in the digestion of carbohydrates. 27

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Pancreatic lipase secretion hydrolyzes Fats into Fatty acid. The complex fluid medium in the duodenum helps to dissolve many drugs with limited aqueous solubility. The duodenum is a site where many ester prodrugs are hydrolyzed during absorption. 28

Jejunum :

Jejunum The jejunum is the middle portion of the small intestine, between the duodenum and the ileum. 29

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Digestion of protein and carbohydrates continues after addition of pancreatic juice and bile in the duodenum . This portion of the small intestine generally has fewer contractions than the duodenum and is preferred for in-vivo drug absorption studies 30

Ileum :

Ileum The ileum is the terminal part of the small intestine . This site has fewer contractions than the duodenum. The pH is about 7, with the distal part as high as 8. 31

Large intestine :

Large intestine Drug absorption at in this region is insignificant as Its length and mucosal surface area is very small . Only a few drugs are absorbed in this region. 32

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The major function of large intestine is absorption of water and electrolytes. The Longer residence time (6 to 1 2hrs) and colonic transit of large intestine important for absorption of poorly soluble drugs and sustained release drugs. 33

Colon :

Colon The colon lacks villi and has limited drug absorption also, because of the more viscous and semisolid nature of the lumen contents. 34

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Colon is lined with mucin that functions as lubricant and protectant. The pH in this region is 5.5 to 7 .0. A few drugs, such as Theophyllin e and Metoprolol , are absorbed in this region. Drugs that are absorbed well in this region are good candidates for an oral sustained-release dosage form. 35

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Due to the presence of bicarbonate secretion , acid drugs will dissolve . Bile secretion helps to dissolve fats and hydrophobic drugs . The ileocecal valve separates the small intestine from the colon 36

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The colon contains both aerobic and anaerobic microorganisms that may metabolize some drugs . For example: L-dopa and lactulose are metabolized by enteric bacteria. 37

Rectum :

Rectum The rectum is about 15 cm long , ending at the anus . In the absence of faecal material, the rectum has a small amount of fluid (approximately 2 mL) with a pH about 7. 38

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The rectum is perfused by the superior middle inferior haemorrhoidal veins. The superior haemorrhoidal vein joins the mesenteric circulation, which feeds into the hepatic portal vein and then to the liver . The inferior haemorrhoidal vein and the middle haemorrhoidal vein feed into the vena cava and back to the heart 39

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Drug absorption after rectal administration may be variable, depending. The placement of the suppository (or) Drug solution within the rectum. 40

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Physiological& pathological characacteristics of patient 41

1. Age :

1. Age In infants GI pH is high and intestinal surface and blood flow to GIT is low as compared to adults results in poor drug absorption. In elderly people, alteration in drug absorption because of Alteration in gastric emptying, Incidents of achlorhydria, Bacterial over growth in small intestine . 42

Gastric emptying :

Gastric emptying D efined, as passage of contents of stomach into the intestine. Rapid gastric emptying is advisable where : Rapid onset action is required, eg; sedatives. Dissolution of drug occurs in intestine. eg; Enteric coated tablets. Drug is unstable in gastric fluids. Drug is best absorbed from distal part of small intestine, eg: vitamin B 43

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Dosage forms Gastric residence time 1.Non -disintegrating monolithic dosage forms 10 to 20 min. 2. Capsules 60 to90min 3.Solutions 20to60min 4.Suspension 20to60min(depending on concentration) 5.Large single unit matrix 1 to 2h 6.Pellet a.)Light pellet b.)Intermediate pellet. c.)Heavy pellet 90-150min(jejunum) 20min 60-300min Gastric residence time of various dosage forms

Kinetics of GI Emptying :  :

Kinetics of GI Emptying : GI emptying is first-order kinetics. Parameters that are used to quantify a gastric emptying; 1.Gastric emptying rate: Is the speed at which the stomach contents are emptied into the intestine. 2.Gastric emptying time: Time required for the GI content to empty into small intestine. 3.G.E.t 1/2 : Is time taken for half the stomach contents to empty. 45

Factors affecting GI emptying :

Factors affecting GI emptying Factors affecting GI emptying 1.Volume of meals 2.Composition of meal 3.Physical state of meal 4.GI pH 5.Body posture 6.Emotional state 7.Exercise 8.Drug s 46

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1.Volume of meal: Larger the bulk of the meal, longer the gastric time and however an initial rapid rate of emptying is observed with large meal volume and initial lag phase in emptying of small volume meals. 2.GI pH: Gastric emptying is retarded at low stomach pH and promoted at alkaline 47

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3.Composition of meal: The rate of gastric emptying for various food materials in the following order carbohydrates>proteins>fats. 4.Physical state: Liquid meal takes less time as compared to solid meals. 48

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5.Temperature of the meal : High or low temperature of the ingested fluid ( in comparison to body temperature ) reduces the gastric emptying rate. 6.Body Posture : Gastric emptying is favoured while standing and by lying on the right side since normal curvature of the stomach provides a downhill path . whereas lying on the left side or in supine position retards it. 49

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7.Exercise: Vigorous physical training retards gastric empting. 8. Emotional state: Stress and anxiety promotes GI motility, where as depression retards it. 9..Drugs: That retards gastric emptying are Antacids, Anti Cholinergic, Narcotic analgesics and tricyclic antidepressants. Metaclopramide, Domperidone and Cisapride stimulate gastric emptying. 50

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10.Eletrolyte and Osmotic Pressure : Water, isotonic solutions and solutions of low salt concentration empty stomach rapidly . Whereas higher electrolyte concentration decreases gastric emptying rate. 11. Disease States: Disease like gastroenteritis , gastric ulcer ,pyloric stenosis, diabetes and hyperthyroidism retard gastric emptying 51

Factors affecting Gastric Emptying:

Factors affecting Gastric Emptying Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to empty more slowly than liquids Type of Meal Gastric emptying rate: carbohydrates > proteins > fats Temperature of Food Increase in temperature, increase in emptying rate Body Position Lying on the left side decreases emptying rate and right side promotes it GIT pH Retarded at low stomach PH and promoted at higher alkaline PH Emotional state Anxiety promotes where as depression retards it Disease states gastric ulcer, hypothyroidism retards it, while duodenal ulcer, hyperthyroidism promotes it. 52

3. Intestinal transit:

3. Intestinal transit Defined as, the residence time of drug in small intestine. As small intestine is major site for absorption of most drugs long intestinal transit time is desirable for drug absorption. The residence time mainly depends on the intestinal motility or contractions 53

Intestinal residence time of various dosage forms:

Intestinal residence time of various dosage forms Dosage forms Intestinal residence time time 1.Non -disintegrating monolithic dosage forms 120to 300 min. 2. Capsules 60 to90min 3.Solutions 158to234min 4.Suspension 120to150min(depending on concentration) 5.Large single unit matrix 1 to 12h 6.Pellet a.)Light pellet b.)Intermediate pellet. c.)Heavy pellet 90-150min(jejunum),20hrs (colon) 20min(stomach) 60-300min 54

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Delayed intestinal transit is desirable for : 1. Sustained release dosage forms eg; cholrothiazide . 2 .Drug that only release in intestine ie ., enteric coated formulations. 55

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3. Drugs absorbed from specific sites in intestine , eg; several B vitamins 4. when the drug penetrate the intestinal mucosa very slowly eg; Acyclovir. 5. when absorption of drug from the colon is minimal. 56

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Intestinal region Transit time Duodenum 5 minutes Jejunum 2 hours Ileum 3 to 6 hrs Caecum 0.5 to1hours Colon 6 to 12hours Transit time for contents from different regions of intestine 57

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Intestinal transit is influenced by several factors like food , drugs and diseases. Food decreased digestive secretions and pregnancy retard intestinal transit whereas diarrhoea promotes it. Drugs like metoclopramide that promote gastric emptying and intestinal transit enhances absorption of rapidly soluble drugs 58

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The GI p H generally increase gradually as one move down the stomach to colon and rectum. A tremendous 10 7 fold difference in the hydrogen ion concentration is observed between the gastric and colon fluids 4. GI pH 59

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GI pH influence in several ways: 1.Disintegration: Disintegrating of some dosage forms is pH sensitive, enteric coated tabs dissolve only in alkaline pH. 2.Dissolution: A large no. of drugs either weak acids or weak bases, their solubility is greatly affected by GI pH. -weakly acidic drugs dissolve rapidly in alkaline pH. -basic drugs soluble in acidic pH.. 60

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3.Absorption: Depending upon drug pK a whether its an acidic or basic drug the GI pH influences drug absorption. 4.Stability of drug: GI pH influence the stability of drug. Eg; erythromycin 61

INFLUENCE OF DRUG pKa AND GI pH ON DRUG ABSORBTION:

INFLUENCE OF DRUG pK a AND GI pH ON DRUG ABSORBTION Drugs Site of absorption Very weak acids ( pK a > 8.0) Unionized at all ph values Absorbed along entire length of GIT Moderately weak acids ( pK a 2.5 – 7.5 ) Unionized in gastric ph Ionized in intestinal ph Better absorbed from stomach Strong acids ( pK a <2.5) Ionized at all ph values Poorly absorbed from git Very weak bases ( pK a < 5 ) Unionized at all ph values Absorbed along entire length of GIT Moderately weak bases ( pK a 5 – 11 ) Ionized in gastric ph Unionized in intestinal ph Better absorbed from intestine Strong bases ( pK a >11) Ionized at all ph values Poorly Absorbed from GIT 62

Blood flow to git :

Blood flow to git GIT is extensively supplied by blood capillary, about 28% of cardiac output is supplied to GIT portion , most drug reach the systemic circulation via blood only. Any factor which affects blood flow to GIT may also affect absorption . 63

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Blood flow is also important for actively absorbed drugs since oxygen and energy is required for transportation. Food influences blood flow to the GIT. Reason: as perfusion rate increases after meal and persist for few hours. 64

Disease state :

Disease state S everal disease state may influence the rate and extent of drug absorption. Three major classes of disease may influence bioavailability of drug. GI diseases CVS disease HEPATIC disease 65

Gastric diseases :

Gastric diseases The influence of achlorhydria (decreased gastric acid secretion and increases stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs . ( decreased absorption e.g. aspirin) has been studied. Two of the intestinal disorders related with malabsorption syndrome that influence drug availability are Celiac disease and Chron’s disease 66

GI diseases :

GI diseases G I infections : 1.Celiac disease: (characterized by destruction of villi and microvilli) abnormalities associated with this disease are increase GI emptying rate and GI permeability, alter intestinal drug metabolism. 2.Crohn’s disease: alter gut transit time and decreased gut surface area. G I surgery: Gastrectomy may cause drug dumping in intestine, osmotic diarrhoea and reduce intestinal transit time. 67

Hepatic diseases:

Hepatic diseases Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that undergo considerable first-pass hepatic metabolism . e.g . propranolol In such cases enhanced bioavailability is also observed 68

Cardio-vascular diseases:

Cardio-vascular diseases In CVS diseases blood flow to GIT decrease, causes decreased drug absorption. Several changes associated with congestive cardiac failure influence bio-availability of a drug viz., Edema of the intestine, Decreased blood flow to the GIT and Gastric emptying rate and Altered GI p H , Secretions and Microbial flora. 69

7. Gastro intestinal contents   :

7. Gastro intestinal contents 1.Food- drug interaction: In general presence of food either delay , reduce, increase or may not affect absorption. Food drug interaction may be due to the influence of food on physiological functions such as alteration in the GI emptying rate GI fluid secretions ph blood flow absorptive process. 70

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physicochemical interaction with drug alteration in drug dissolution profile complexation adsorption. Generally drugs are better absorbed under fasting conditions and presence of food retards or prevent it 71

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Delayed or decreased drug absorption due to food: A.) delayed gastric emptying affecting unstable drugs in stomach B.)formation of poorly soluble unabsorbable complex C.) increased viscosity 72

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Increased drug absorption following a meal: A.)increased time for dissolution of a poorly soluable drug. b.) enhanced solubility due to git secretion like bile. C)prolong residence time. D.)increased lymphatic absorption. 73

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2.Interaction of drug with normal GI contents: GIT contains number of normal constituents such as mucin, bile salts and enzymes , which influence the drug absorption. Eg; Inhibitory action of bile on GI motility 74

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3.Fluid volume: administration of drug with large fluid volume results in Better dissolution Rapid gastric emptying Enhanced absorption. eg; erythromycin is better absorbed with glass of water under fasting condition than with meal; 75

3.Drug-Drug interaction in the GIT:

3.Drug-Drug interaction in the GIT Adsorption: Eg; Anti diarrheal preparations contains adsorbents like kaolin, prevents a absorption of many drugs co-administered with them. Complexation: Eg; Penicillin derivative with ca- gluconate . pH changes: Basic drugs changes gastric pH Eg; Tetracycline with antacids. 76

Physiological drug- drug interaction :

Physiological drug- drug interaction Decreased GI transit : Anticholinergic such as propanthelin e retard Gi motility and drugs like Rantidine and Digoxin promote absorption . whereas delay absorption of Paracetamol and Sulphamethoxazole INCRESED GASTRIC EMPTYING: Metoclopramide promotes GI motility and enhances absorption of tetracycline , pivampicillin, levodopa. 77

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Altered GI metabolism : Antibiotics inhibit bacterial metabolism of the drugs . eg: Erythromycin enhances efficacy of digoxin by the mechanism . Coadminitration of antibiotics with oral contraceptives like ( Ethinylestradiol )decreases the efficacy of oral contraceptives by decreasing enterohepatic cycling of steroid conjugates. 78

Interaction of drugs with components of the GIT:

Interaction of drugs with components of the GIT a.) Mucin The mucosal surface of stomach and intestin e are covered with layer of a vicid mucopolysaccharide called mucin. The physiological function of mucin is to protect gastric mucosal cells of stomach from damaging effect of gastric fluids and enzymes. 79

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b)Bile salts : The bile salts present in the biliary secretion and deposited in the small intestine may have a pronounced influence on drug absorption. The surface active bile salts may enhance the dissolution rate of poorly soluble drugs and thereby promote intestinal absorption 80

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C)Enzymes and proteins: The various enzy mes and other proteins in the gastrointestinal tract are capable of interacting with drugs in a number of possible ways . Such as ; pancreatin and trypsin deacylates N-acetyl sulfisoxazole and n- acetylsulfisoxazole . Proteinaceous materials have been shown to reduce the activity of aluminium antacids by a complex interaction . 81

 First pass metabolism :

First pass metabolism The loss of drug through biotransformation by eliminating organs(liver) during its passage to systemic circulation is known as first pass metabolism To systemic circulation Drug dose Destroyed in gut Not absorbed destroyed Destroyed in gut wall Destroyed by liver 82 Process that reduces the availability of orally administered drugs

 First pass metabolism :  :

First pass metabolism : Four primary systems which affect presystemic metabolism of a drugs . 1. Luminal enzymes. Digestive enzymes Bacterial enzyme. 2.Gut wall enzymes (or )mucosal enzymes. 3.Hepatic enzymes 83

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Luminal enzymes: These are enzymes present in gut fluids and include enzymes from intestinal and pancreatic secretions. Pancreatic secretions contain hydrolases, peptidases Chloramphenicol palmitate hydrolases into active chloramphenicol Peptidases inactivate protein /polpeptide drugs 85

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G ut wall enzymes : Also called mucosal enzymes they are present in gut and intestine, colon. Stomach mucosa contains Alcoholic dehydrogenase Intestinal mucosa contain both phase 1 and phase 2 enzymes Colonic mucosa also contain both phase 1 and phase 2 enzymes 86

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B acterial enzymes : GI microflora scantily present in stomach and small intestine and is rich in colon. So orally administered drugs remain unaffected by them. Colonic microbes render drug more active or toxic on biotransformation. Intestinal micro flora has important role in the enterohepatic cycling 87

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Hepatic enzyme : Several drug undergo first-pass hepatic metabolism, highly extracted ones being Isoprenaline , Nitroglycerin , Morphine, Dilitiazem , Morphine , Lidocaine , Nifedipine. 88

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REFERENCES Brahmankar D.M., Jaiswal S.B.,“Absorption of Drugs” Biopharmaceutics and Pharmacokinetics – A treatise,1st edition Vallabh Prakashan, Delhi, 1995,. Shargel L., Andrew B.C., Fourth edition “Physiologic factors related to drug absorption” Applied Biopharmaceutics and Pharmacokinetics, Prentice Hall International, INC., Stanford 1999. 4th edition. Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma or serum and amount of drug in the body, J. Pharm.Sci., 58, 1969, 193-197. Venkateswarlu,V. Biopharmaceutics and Pharmacokinetics, Second edition,2010, 89

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Heartly thanks to Prof .Dr. M.B.Venkatapathi Raju Sir,Principal,SRCP . Prof . G.Sudhakar sir , Vice principal,SRCP . Prof .Dr.R. Santosh Kumar sir , H.O.D,SRCP. My Teachers and other faculty members and non teaching staff , SRCP . Finally special thanks to Srinivasa Rao College of Pharmacy Management. 90

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