By

Mr. Harshad Govind Salpe

Guide

Dr. N. J. Duragkar

Sharad Pawar College of Pharmacy

Wanadongri, Hingna Road,

Nagpur-441 110 [M.S.]

2013-2014

ABSORPTION OF DRUGS

DEFINATION

Drug absorption is defined as the process of movement of

uncharged drug from the site of administration to the systemic circulation.

Absorption can also be defined as the process of movement

of uncharged drug from the site of administration to the site of measurement i.e. plasma

Route of absorption

The EnteralRoute

The ParenteralRoute

The Topical Route

GASTROINTESTINAL ABSORPTION OF DRUG

Movement of drug across the one or more biological membrane is called as drug transport.

CELL MEMBRANE STRUCTRE AND PHYSIOLOGY

• Double layer of

amphiphilic phospholipidmolecules

• Hydrophobic core

• Hydrophilic head

• Mayonnaise sandwich

• Aqueous filled pores or perforations of 4-10 A0 in diameter present

MECHANISMS OF DRUG ABSORPTION

•Passive diffusion•Pore transport•Facilitated diffusion•Active transport•Ion or electrochemical diffusion•Ion-pair transport •Endocytosis

PASSIVE DIFFUSION

•Non ionic diffusion•No energy source required•Process for >90% of the drug•Based on Fick’s law•Driving force – concentration or electrochemical gradient

Fick’s law

Drug molecule diffuse from a region of higher concentration to one of lower

concentration until equilibrium is attained and that the rate of diffusion is directlyproportional to the concentration gradient across the membrane.

dQ/dt = DAKm/w (CGIT – C)

h

PORE TRANSPORT•Also called as convective transport, bulk flow or filtration •No energy source required•Process for low molecular weight, low molecular size & water soluble drug •Molecular weight upto 400 daltons be absobed•Ex- sugar, water, urea•Driving force – hydrostatic pressure or osmotic differences across membrane •Importance for renal excretion

CARRIER-MEDIATED

TRANSPORT•Carriers may be enzyme or some other component of the membrane •Carriers binds reversibly or noncovalently with solute molecules•Ex- monosaccharides, amino acids & vitamines

IMPORTANT CHARACTERISTICS •Structure specificity•Drug having Structure similar to essential nutrients called false nutrients •Ex- Antineoplastic agents like 5-fluorouracil & 5-bromouracil •No. of carrier limited – competition between agents having similar structure•System is capacity limited •Mixed order kinetics also called Michaelis-Menten, saturation or non linear kinetics•Site specific (absorption window)

Concentration of drug at the absorption site

Rat

e o

f d

rug

abso

rpti

on

Carrier-mediated transport

Passive diffusion

FACILITATED DIFFUSION

•Carrier mediated transport system that operates Down the concentration gradient (Downhill transport)

•Faster than simple passive diffusion

•Driving force- Concentration gradient

•No energy expenditure is involved

•Ex- entry of glucose in RBC & intestinal absorption of Vitamins B1 & B2

ACTIVE TRANSPORT•More important process than facilitated diffusion.

•Against the concentration gradient or uphill transport

•energy is required

•As the process requires expenditure of energy, it can

be inhibited by metabolic poisons that interfere with

energy production

•A few lipid-insoluble drugs that resemble natural

physiologic metabolites E.g. 5-fluorouracil are

absorbed from the gastrointestinal tract by this process

•Endogenous substance that are transported – sodium,

potassium, calcium, iron, glucose, certain amino acid

& vitamins like niacin, pyridoxin, ascorbic acid

IONIC OR

ELECTROCHEMICAL DIFFUSION

•Charge on membrane influences permeation of drugs

•Order of permeation – unionized molecule > anions > cations

•Driving force – potential deference or electrical gradient

ION-PAIR TRANSPORT

Membrane

Passive diffusion

BloodGI lumen

___+ ++

Cationic drug

Endogenous anion

Neutral ion-pair complex Free drug

•Quaternary ammonium ion compounds & sulfonic acid ionized under all pH conditions •Endogenous ion – mucin

ENDOCYTOSIS

• Engulfing extracellular material

• Responsible for the uptake of macromolecular nutrients like fats & starch, oil soluble vitamins like A, D, E, K and drug such as linsulin

• In endocytosis, there are three process:

A) Phagocytosis

B) Pinocytosis

C) Transcytosis

Phagocytosis

(cell eating) adsorptive uptake of solid particulates

Pinocytosis

(cell drinking) uptake of fluid solute

This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

Transcytosis

It is a phenomenon in which endocytic vesicle is transferred from one extracellular compartment to another.

FACTORS INFLUENCING DRUG ABSORPTION AND BIOAVALILABILITY

BIOPHARMACEUTICAL CONSIDERATIONS IN

DOSAGE FORM DESIGN

THE PROCESS CONSISTS OF FOUR STEPS

•Disintegration of the drug product

•Disaggregation and subsequent release of the drug

•Dissolution of drug in the aqueous fluids at absorption site

•Movement of the dissolve drug through the GI membrane into the systemic circulation and away from absorption site

Slowest step is called rate-determining or rate-limiting step (RDS)

FACTORS AFFECTING DRUG ABSORPTION

A PHARMACEUTICAL FACTORS1. Physiochemical properties of drug substances• Drug solubility and dissolution rate • Particle size and effective surface area • Polymorphism and amorphism• Pseudopolymorphism (hydrates/solvates)• Salt form of drug • Lipophilicity of drug • pKa of the drug and pH• Drug stability

2. Dosage form and characteristics and pharmaceutic ingredients• Disintegration time• Dissolution time • Manufacturing variables• pharmaceutic ingredients (excipients/ adjuvants)• Nature and type of dosage form• Product age and storage conditions

A PATIENT RELATED FACTORS1. Age2. Gastric emptying time3. Intestinal transit time4. GI pH5. Disease state 6. Blood flow trough GIT7. GI contents • Other drug• Food• Fluids• Other GI contents 8. Presystemic metabolism by • Luminal enzymes• Gut wall enzymes• Bacterial enzymes• Hepatic enzymes

FACTORS AFFECTING DRUG ABSORPTION

PHYSIOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION

Drug solubility and dissolution rate

The rate determining steps in absorption of orally administered

drugs are:

1. Rate of dissolution 2. Rate of drug permeation through the biomembrane.

Dissolution is rate determining step for hydrophobic & poorly

aqueous soluble drugs. E.g. Griesiofulvin & Spironolactone.

Permeation is the rate determining step for hydrophilic & high

aqueous soluble drugs.E.g. cromolyn sodium OR Neomycin.

Solid

dosage

form

Solid

drug

particles

Drug in

solution at

absorption

site

Drug in the

body