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ADME – Pharmacokinetics

· The study of the time course of drug

concentrations in the body

· Provides practitioners with a useful

tool to design optimally beneficial drug dosage schedules for each individual

patient

· In food animals – PK is used to

determine withdrawal to protect consumers being exposed to drug residues

Membrane barriers directly or indirectly define the nature of compartments or

other mathematical modules in pharmacokinetic models.

· the most effective barriers are those

that protect the organism from the outside world, eg., stratum corneum, GI

tract and respiratory tract

· the interstitial fluid is a common

compartment through which any drug must transit after absorption en route to

the bloodstream, or after delivery by blood to a tissue on route to a cellular

target

· capillary membranes between the

tissue and the blood are relatively porous and have large fenestrae to allow

for large molecules to pass through

· membranes define homogenous tissue compartments

and must be traversed in all processes of absorption and disposition

All cellular

membranes are primarily lipid bilayers with proteins embedded into the surface

· they are arranged with hydrophilic

(polar) head groups on the surface and hydrophobic (non-polar) tail groups on

the inside

· the location of proteins is primarily

a consequence of their hydrophobic regions residing in the lipid interior and

hydrophilic and ionic regions occupying the surface à thermodynamically the most stable

configuration

o

some

of them are for enzymatic transport

· changes in fluidity of lipds can alter

protein configurations à this is the mode of action for gaseous anaesthetics

· most drugs cross lipid membranes by

passive diffusion

For

absorption or distribution of a drug to occur, a lipid membrane must be sojourned

·

in some

sites and in fenestrated capillaries, pores exist to allow for the flow of some

small molecules

·

other sites

– eg. Brain, CSF – additional membranes have to be traversed – an additional

protective mechanism

·

drug

characteristics that promote transmembrane diffusion favour drug action and

effect à lipophilic compounds have increased absorption and distribution

throughout the body

Elimination

organs operate on a similar principle

·

primary

mechanism for a drug to be excreted by the body is to become less lipophilic à more hydrophilic à this is a property required for excretion in aqueous fluids

of the renal or biliary systems

·

when

hydrophilic drugs are injected into the bloodstream they are typically

minimally distributed and quickly excreted by the renal or biliary system

·

very

lipophilic compounds can be converted into hydrophilic ones through liver

metabolism à being more hydrophilic means that distribution is restricted and excretion

is more readily achieved

Drug passage across membranes