Absorption and distribution are influenced by the formulation
– To reach their sites of action, drugs must overcome physiological barriers.
Mechanisms of Drug Absorption
– The passage of small water-soluble substances
through aqueous channels
» A function of hydrostatic or osmotic
differences across the biological membrane.
• Passive diffusion
• Requires passage across biological membranes
– The passage of larger drug molecules across
» A function of the concentration gradient of the
drug across the membrane
• Facilitated transport
– The drug forms a complex with a component of the biological membrane
» The complex is carried through membrane, the drug is released, and the carrier molecule returns to the membrane surface
» Does not require energy
» Does not proceed against a concentration gradient.
– The drug forms a complex with a component of the biological membrane
» Characterized by selectivity, saturability, and competitive inhibition
» Requires energy
» Moves against a concentration gradient.
– Some water-insoluble substances are engulfed by the cell membrane and are released into the cytoplasm
Ex. Uptake of fats, starch, vitamins A,D,E,K, insulin.
Drug absorbed into lymphatic circulation bypassing first pass metabolism.
Absorption of drugs by various mechanisms
– Most drugs are weak acids or weak bases
• Cross biological membranes mainly by passive diffusion
– Factors affecting the rate of diffusion:
» Molecular weight
» Concentration gradient of the drug across the
» Thickness, surface area, and permeability of
• A prerequisite for establishing adequate plasma drug levels.
Drug Absorption - Passive Diffusion
• Most common means of drug absorption
• Rate of passive diffusion across biological membranes is dependent upon:
– Concentration difference across membrane
• Usually very large
• Relatively constant for most drugs (100-500 MW)
• Variable (-OH, C=O)
– I onization
• Variable for drug (-COOH, -NH3)
• Variable for environment (stomach, pH 1-3; duodenum,
pH 5-7; rest of sm. intestine, pH 7-8)
• Majority of oral drug absorption occurs in duodenum.
Physiological Factors Affecting Oral Drug Absorption
1) Gastrointestinal Motility
– Decreased stomach emptying slows drug absorption
– Can be decreased by food, disease, drugs (opioids)
2) Gastrointestinal Blood Flow
– Removes drug from site of absorption (conc. gradient)
– Limiting factor for highly absorbed drugs (e.g. ethanol)
3) Surface area
– Approx 250m 2 (adult male); 1000x > stomach
– Most drug absorption occurs in small intestine (esp. duodenum)
4) Metabolism and Efflux
– Many drugs are metabolized in the intestinal wall
– Many drugs are effluxed from enterocytes to gut lumen by transport proteins
5) Changes in pH of Gastrointestinal Tract
– Affects polarity of drug
– Can be altered by food, disease, other drugs (e.g. antacids)
Drug Absorption - Summary
• Most drug absorption occurs through passive absorption.
• Lipid soluble drugs are more readily absorbed than non-lipid soluble drugs.
• Non-ionized drugs are more readily absorbed than ionized drugs.
• Weak acids or weak bases are more readily absorbed in the small intestine than strong acids and bases.
Stronger acids can be absorbed in stomach.
• Most drug absorption occurs in the small intestine.
- Large surface area
Bioavailability refers to the rate and extent of absorption of a drug from dosage form.
It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.
BA = Quantity of drug reaching systemic circulation
Quantity of drug administered
– IV = 100%
– Oral < 100%
– Other routes ≤ 100%
– Example: Cyclosporine
• Bioavailability IV = 100%
• Bioavailability Oral = 25%
• Therefore, oral dose 4 x IV dose
Major Factors Affecting Drug Bioavailability
• First-Pass Metabolism (liver
• Efflux from enterocytes (active
• Physiochemical properties of
drug that affect absorption
(polarity, size, etc)
• Nature of drug formulation
(binders, solubilizers, etc)
IV administration circumvents
• Process by which a drug reversibly leaves the site of administration and distributed throughout the tissues of the body
• A prerequisite for most drugs to reach target organs in therapeutic concentrations
– Drugs, once again, must overcome physiological barriers
» simple capillary endothelial barrier
» simple cell membrane barrier
» Blood-brain barrier
» Blood-placental barrier
» CSF barrier
» Blood-testis barrier
Extent is dependent upon various factors
– Blood flow (lung, kidney, liver > brain, skeletal muscle > adipose, bone) – Ability of drug to traverse biological membranes.
– Organs and tissues vary widely in the proportion of blood flow
» Heart, liver, kidney, CNS receive the drug within minutes
» Muscle, most viscera, skin, and fat require longer time
– Degree of binding to blood proteins (e.g. serum albumin)
• Distribution of drug to target organ/site is a critical requirement for achieving a therapeutic benefit, but
• Drug will be active at any organ/site if the receptor for the drug is present and the drug achieves a sufficient local concentration. • e.g. Aspirin has analgesic effect in brain for headache relief and can also cause unwanted effects at other sites at common doses (e.g. GIT bleeding).
Drugs that selectively bind to plasma proteins/other blood components ex warfarin (less bound to extravascular tissues) have app Vd less than their real Vd.Vd of warfarin 10litres
Drugs that bind selectively to extravascular tissues (less bound to blood and blood components) ex.chloroquine have app Vd greater than their real Vd.Vd of chloroquine 15000litres.these drugs leave the body slowly and generally more toxic.
Distribution - Special Considerations
• Consequence of physiochemical properties of drug and unique
physiological properties of organ/tissue
• Tetracycline has high affinity for calcium.
• Iodine-containing drugs are transported into this organ.
• Blood-brain barrier excludes most drugs
• Can accumulate large amounts of lipid-soluble drugs
• Release back into systemic circulation can occur with weight loss
Distribution - Plasma Protein Binding
• Many drugs bind reversibly with proteins in blood and other tissues
• Binding to serum albumin in the blood is a common occurrence for drugs (especially lipophilic drugs)!
Drug + Pr otein " Drug • Pr otein
• Albumin bound drug is not available to reach therapeutic target.
• Albumin bound drug can act as a reservoir of drug.
• Amount of free drug can be increased by:
– Displacement by another drug.
– Reduction of serum albumin levels (disease).
– Theoretically important for very highly bound drugs (>90%).
• In practice, no clinically relevant examples
– Many drugs are
bound to plasma
» Volume of =
• Most drugs are lipophilic and only partially ionized at physiological pH
– Organic compounds; Optimized for oral absorption
• Lipohilic drugs are poorly excreted by the kidney and liver
– Binding to plasma proteins inhibits glomerular filtration
– Reabsorption at renal tubules and biliary epithelium
– Partitioning into lipid-rich tissues (e.g. adipose)
• Biotransformation increases polarity and water solubility
• Metabolites often have less pharmacological activity; some drugs (prodrugs) have more active or toxic metabolites (bioactivation)
• Liver is the major site for biotransformation of drugs; Intestine also has significant metabolic capacity for some drugs (first-pass effect)
• Biotransformation can be divided into Phase I and Phase II metabolism
• Metabolism fosters biotransformation into
more polar, more water-soluble fractions
– Phase I (nonsynthetic reactions)
» Cytochrome P450-dependent oxidation
» Cytochrome P450-independent oxidation
– Phase II (synthetic reactions)
» Transfer enzymes, both in the cytosol and the
ER of hepatocytes, couple (conjugate) drugs
to endogenous macromolecules
Phase I/ functionalisation/asynthetic reactions
Phase II/synthetic/ conjugation reactions
Phase I reactions: polar functional groups like OH, COOH, NH2, and SH groups are introduced.These include oxidative, reductive, and hydrolytic reactions.
These reactions increase hydrophilicity .
Reduce stability .
Phase II reactions: These reactions involve covalent attachment of small polar endogenous molecules such as glucuronic acid, sulphates, glycine to either unchanged drugs or phase I products bearing functional groups like OH, COOH, NH2 and SH groups.
Phase I metabolite may not be hydrophilic or may be pharmacologically inert but conjugation generally result in total loss of activity and high polarity .
Hence metabolism converts lipophilic water insoluble nonpolar drugs into polar and water soluble products that can be easily excreted by body.
Biotransformation is essentially a detoxifying process.