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Gastrointestinal absorption of drugs and its biological considerations
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Gastrointestinal absorption of drugsGastro intestinal barrier( lipoidal sieve) that
separates lumen of the stomach and intestine is a semi permeable membrane, permitting the rapid and limited passage of some compounds.
Gastro intestinal absorption is more for some nutrients
glucose, amino acids, fatty acids &vitamins etc.
lipid molecules and some hydrophilic molecules are readily absorbed from git in passive manner where as large polar molecules absorbed by active manner.
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Mechanism of gastro intestinal absorption
Passive diffusion
Carrier mediated absorption
Active Facilitated
Endocytosis
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Passive Diffusion :
Membrane transport of drug and other chemicals directly through the lipid or aqueous channel is called passive diffusion
It follows FICKS FIRST LAW of diffusion.
It states drug molecule diffuses from a region of higher conc. to the lower conc. until equilibrium is attained.
dc/dt = k(C1-C2).
dc/dt : rate of diffusion
C1C2 = drug concentrations on each side of the membrane.
K= proportionality constant.
Most of the drugs follows first order kinetics.
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Pore transport and ion pair transport:It is also called as convective transport, bulk
flow or filtration. the process is important in the absorption of low molecular weight(less than100),low molecular size(smaller than diameter of the pore).for eg-urea,water,and sugars.
Ion-pair transport-that explains the absorption of drugs like quaternary ammonium compounds and sulphonic acids, which ionize under all PH conditions, is ion –pair transport. 5
Carrier Mediated Transport :
The compound involved is called CARRIER.
The carrier binds non covalently or reversibly with solute molecule to be transported.
It is specialized transport mechanism with out which many essential water soluble nutrients like mono -saccharides will be poorly absorbed.
The carrier solute molecule complex travel across the membrane to other side where it dissociates and discharges the solute molecule and travels back.
It follows mixed order kinetics. 6
Facilitated diffusion:
This carrier mediated transport system that operates down the concentration gradient (down hill transport).
It is faster than passive diffusion.
Driving force is conc. gradient.
Ex: vitamins.
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Active Absorption:
It requires energy in the form of A.T.P.
Takes place in the intestine
This is a UP HILL TRANSPORT.
Ex: Na,Ca,Fe, glucose, galactose, AA, Bile salts.
Rate of absorption = VmaxC/Km+C.
C=solute conc. at the absorption site.
Vmax and Km are const.8
Endocytosis:It is a minor transport mechanism which
involves engulfing extracellular materials within a segment of cell membrane to form a saccule or a vesicle.
This phenomenon is responsible for the cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins & water soluble vitamins.
It include two type of processes:
Phagocytosis(cell eating): absorptive uptake of solid particulates.
Pinocytosis (cell drinking): uptake of fluid solute.
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BIOLOGICAL FACTORS :
Age
Gastro intestinal physiology.
Gastro intestinal blood flow.
Gastro intestinal PH.
Gastric emptying.
Effect of food on drug absorption.
Disease states
Presystemic metabolism
Mal absorption.
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AGE :In infants, the PH gastric is high and
intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults.
In elderly person,causes of impaired drug absorption include altered gastric empting, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial overgrowth in small intestine.
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Gastro Intestinal Physiology :STOMACH :
It is a pouch like structure lined by smooth epithelial membrane.Absorption of weekly acidic drugs or un ionized drugs and week basic drugs takes place.
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Small intestine :
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generally carrier mediated transport is seen in most drugs.Proximal part-
absorption of dietary constituents includes mono saccharides, vitamins, minerals etc. Ileum-Vit B12, bile
salts.
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Micro villi :
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The effective surface area can be made 10 times larger to that of stomach because of the presence of micro villi.These are finger like projections arising from and forming folds in intestinal mucosa.ESA was decreasing from proximal part to distill part of small intestine.
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Large intestine :Click to edit Master
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ESA was less.It is not an effective siteIn complete absorption was occurred when large amount of drug reaches colonIts an area of absorption of escaped drugIt was recommended for certain drugs whose metabolism occurred by intestinal bacteria for bio activation.
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BLOOD FLOW :
It plays a major role in absorption by continuously maintaing the concentration gradient across the epithelial membrane.
Absorption of polar molecules doesn’t depends on the blood flow.
Rate of drug absorption is un effected by mesenteric blood flow.
Absorption of lipid soluble molecules highly depends on the blood flow.
Enter blood liver systemic circulation
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Gastro intestinal PH :
PH varies according to the site.
Many drugs are week organic acids or bases so PH is the imp factor.
Gastric fluid retards week basic drugs.
and promotes weekly acidic drugs.
Gastric secretions having PH less than 1.
It varies because of diet and dilution.
ex: penicillin-------------carindacillin
erythromycin--------erythromycinesfolate17
Gastric emptying :
The passage of food from the stomach to the small intestine is called gastric emptying.
This process increases the bioavailability of the drug because mostly the absorption occurs in small intestine.
Slow gastric emptying can delay the onset of effect of the drug Ex: Analgesics & sedatives
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FACTORS EFFECTING GASTRIC EMPTYING :
Volume of meal.
Drugs
Posture
Composition of meal.
Physical state.
Temperature.
PH.
Disease state. 19
Effect of food on drug absorption :
Food stimulate hepatic blood flow, which have implication for the bioavailability of the drug.
Food tends to decrease the rate of gastric emptying which effects drugs like penicillin
Forms poorly soluble and un absorbable complexes.
High protein food causes poor absorption of drugs. ex: levodopa.
High fat food causes poor absorption of drugs. ex:isotertinonin.
Administration of drug with large fluid volume enhances the dissolution rate and gastric emptying.
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Disease states :There are three classes of disease state
1. Gastrointestinal diseases –It influence drug absorption pattern, namely:
Altered GI motility:
Gastrointestinal diseases and infections
Gastrointestinal surgery
2. Cardiovascular diseases
3.Hepatic diseases 21
Presystemic Metabolism:
The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulation is called as first pass or presystemic metabolism.
The 3 primary system which affect presystemic metabolism of a drug are :
Luminal enzymes : the metabolism by these enzymes are categorized into two-
Digestive enzymes, and Bacterial enzymes.
Gut wall enzymes/mucosal enzymes.
Hepatic enzymes.
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Mal absorption :
It is a disorder with impaired absorption of fat, protein, carbohydrate, vitamin, minerals& water.
Drugs which induce mal absorption:
N Neomycin.eomycin.
Phenytoin.
Amino salicylate
These drugs mainly damages the gastro intestinal epithelium emphasis the function of mucosa to serve as a barrier to large polar molecule.
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Mal absorption
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References: Biopharmaceutics and pharmacokinetics by
madan published by Jaypee publication 1st edition page 62-67.
Essentials of Biopharmaceutics and pharmacokinetics by Ashutosh kar,published by Elsevier health sciences 2010 page no-642-657.
Biopharmaceutics and pharmacokinetics by D.M.Brahmankar and Sunil B.Jaiswal ,vallabh Prakashan ,second edition ,page no-65-78.
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Thank you
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