(29) Recap: Bioavailability, Dissolution and Membrane Transport

Bioavailability definition

Quantitative measure of the amount of a drug that reaches its site of action and the rate at which it gets there

Pharmacokinetics definition

What the body does to the drug

Pharmacodynamics definition

What the drug does to the body

LADME in pharmacokinetics

Liberation Absorption Distribution Metabolism Excretion

Liberation in drug kinetics

Drug dissolves at the administration site

Absorption in drug kinetics

Drug crosses biological membranes to reach blood

Two steps for drug appearance in blood after extravascular administration

Release and Absorption

Step that controls overall rate of absorption

The slowest step controls overall rate of absorption

Noyes Whitney equation role

Describes the overall rate of dissolution at constant temperature

Dissolution process steps

Solvation at the crystal surface and diffusion of dissolved molecules into bulk solution

Meaning of Cs in Noyes Whitney

Solubility of the drug

Meaning of S in Noyes Whitney

Surface area of the particle

Meaning of D in Noyes Whitney

Diffusion coefficient of the drug in the dissolution medium

Meaning of h in Noyes Whitney

Thickness of the diffusion layer

Factors affecting dissolution rate

Surface area particle size solubility diffusion coefficient and diffusion layer thickness

Effect of increasing surface area on dissolution

Increases dissolution rate

Effect of pH on weakly acidic drug solubility

Solubility increases at higher pH as the drug becomes ionized

Effect of pH on weakly basic drug solubility

Solubility increases at lower pH as the drug becomes ionized

Intrinsic solubility S0 definition

Solubility of the free unionised form of a drug

Transcellular pathway definition

Drug transport across the cell membrane through the cell interior

Paracellular pathway definition

Drug transport between cells via cell cell junctions

Main pathway of drug absorption

Passive diffusion

Passive diffusion characteristics

Solutes move down a concentration gradient without energy input

Requirement for passive diffusion

Drug must partition into and out of the lipid bilayer

Aqueous pore definition

Hydrophilic channel formed by aquaporin proteins

Molecules using aqueous pores

Small neutral solutes such as urea and glycerol

Facilitated diffusion characteristics

Selective carrier mediated transport down a concentration gradient without energy

Active transport characteristics

Selective carrier mediated transport that can move drugs against a concentration gradient and requires energy

Example of actively transported drug

Levodopa

Flux definition in membrane transport

Rate of drug transport across a membrane

Effect of membrane surface area on flux

Flux increases as membrane surface area increases

Effect of membrane thickness on flux

Flux decreases as membrane thickness increases

Effect of concentration gradient on flux

Flux is directly related to the difference in drug concentration across the membrane

Ficks First Law main idea

Flux is proportional to concentration gradient partition coefficient diffusion coefficient and membrane area and inversely proportional to membrane thickness

Parameters in Ficks First Law

Partition coefficient concentration gradient membrane area diffusion coefficient and membrane thickness

Reason small intestine is main site of absorption

Large surface area due to villi and microvilli and relatively thin epithelium

Reason skin is a poor absorption site

Stratum corneum is thick and presents high diffusion barrier

Partition coefficient K definition

Ratio of drug concentration in a lipid phase to that in an aqueous phase

Meaning of high partition coefficient

K value greater than one indicates preference for the lipid phase

Oil water partition coefficient expression

K equals concentration in oil divided by concentration in water

Octanol water partition coefficient use

Used as a standard measure of drug lipophilicity

Log P definition

Base ten logarithm of the octanol water partition coefficient

Drug ten times more lipid soluble than water soluble P and log P

P equals ten and log P equals one

Drug one hundred times more lipid soluble than water soluble P and log P

P equals one hundred and log P equals two

Drug five times more water soluble than lipid soluble P and log P

P equals zero point two and log P is approximately minus zero point seven

Effect of lipophilicity on absorption

Some lipophilicity is required for a drug to cross cell membranes

Problem with very high lipophilicity

Drug may accumulate in fatty tissue and clear slowly

Role of polar functional groups in drugs

Enable hydrogen bonding to receptors and enzymes

Un ionised drug form properties

Lipophilic form with optimal membrane transport

Ionised drug form properties

Hydrophilic form with reduced membrane transport

Nature of most drugs regarding acidity

Most drugs are weak acids or weak bases

Definition of pH partition hypothesis

Drug accumulates on the side of a membrane where the pH favours its ionised form

Reason ion trapping occurs

Ionised drug form crosses membrane poorly and becomes trapped where ionisation is favoured

Key limitation of pH partition hypothesis about ionised drugs

Assumes ionised drugs are not absorbed even though they can be absorbed to some extent

Other limitations of pH partition hypothesis

Does not account for epithelium type surface area residence time active transport mass transfer or ion pair formation

Effect of type of epithelium on absorption

Permeability varies between tissues such as intestine and skin

Effect of surface area on absorption

Greater surface area increases extent and rate of absorption

Effect of residence time on absorption

Longer contact time at the site allows more drug to be absorbed

Ion pair formation effect

Charged drugs may pair with opposite charges to form neutral species that cross membranes better

Definition of Lipinskis Rule of Five

Qualitative rule predicting likelihood of good oral bioavailability based on physicochemical properties

Lipinski molecular weight criterion

Molecular weight should be less than or equal to five hundred

Lipinski log P criterion

Log P should be less than or equal to five

Lipinski hydrogen bond donor criterion

No more than five hydrogen bond donors

Lipinski hydrogen bond acceptor criterion

No more than ten hydrogen bond acceptors

Purpose of Lipinskis Rule of Five

To identify drug candidates with a good chance of adequate oral bioavailability

Scenario rapid release and slow membrane transport

Hydrophilic drug released quickly but crosses membrane slowly

Best strategy when release is rapid but transport is slow

Modify drug structure to increase lipophilicity rather than changing formulation

Scenario slow release but easy membrane permeation

Lipophilic drug dissolves slowly but crosses membrane readily

Best strategy when dissolution is slow but permeation is easy

Optimize dosage form to enhance dissolution and release

Dissolution step one

Solvation of drug molecules at the crystal surface forming a saturated stagnant layer

Dissolution step two

Diffusion of dissolved molecules from the stagnant layer into bulk solution

Overall rate determining step in dissolution

The slower of solvation or diffusion controls overall dissolution rate

What controls overall rate of absorption

The slowest of dissolution and membrane transport

Meaning of concentration gradient for diffusion

Difference in drug concentration between two sides of a membrane

Clinical relevance of small intestine surface area

Large area enhances absorption of orally administered drugs

Clinical relevance of skin barrier

Thick barrier restricts systemic absorption from topical formulations

Why bioavailability is important

Determines the extent and rate at which drug reaches its site of action influencing therapeutic effect

Use of dissolution enhancement in formulation

Improves release and absorption of poorly soluble lipophilic drugs

Relationship between solubility and dissolution rate

Higher solubility generally leads to faster dissolution

Impact of particle size reduction

Smaller particles increase surface area and thus increase dissolution rate

Role of diffusion layer thickness in dissolution

Thinner diffusion layer increases dissolution rate

Effect of stirring on diffusion layer thickness

Increased agitation reduces diffusion layer thickness and increases dissolution rate

Definition of drug release from dosage form

Process by which drug becomes available in solution at the absorption site

Definition of absorption site

Location where drug crosses biological membranes into the systemic circulation

Why not all orally administered drug reaches systemic circulation

Losses due to incomplete dissolution poor permeability metabolism and efflux

Clinical relevance of Lipinskis rules

Used in early drug design to avoid candidates with poor likely oral absorption

Why rules are called Rule of Five

Physicochemical cutoffs are multiples of five

Relationship between lipophilicity and distribution

Highly lipophilic drugs may partition extensively into fat and membranes

Effect of hydrophilicity on distribution

Hydrophilic drugs tend to stay in aqueous compartments and cross membranes poorly

Optimal balance for oral drugs

Balance between lipophilicity for membrane crossing and polarity for solubility and target binding

Key determinant of passive diffusion rate

Combination of concentration gradient lipophilicity membrane area and thickness

Why energy is not required for passive diffusion

Process is driven by movement toward equilibrium of concentrations

Why active transport can move drugs against gradient

Uses energy often from ATP hydrolysis to drive carrier cycling

Importance of carrier selectivity

Determines which drugs or substrates can be transported by a given transporter

Reason clinical dosing may consider pH

Changes in gastrointestinal pH can alter drug ionisation solubility and absorption

Ionisation state of weak acid in acidic environment

Predominantly un ionised and more membrane permeable

Ionisation state of weak base in acidic environment

Predominantly ionised and less membrane permeable

Ionisation state of weak acid in basic environment

Predominantly ionised and more soluble in aqueous phase

Ionisation state of weak base in basic environment

Predominantly un ionised and more membrane permeabl