Pharmacokinetics: is the fate of drugs within the body ,It involves drug :
or it what hte body does to the drug
ADME:– Absorption, Distribution, Metabolism, Excretion.
>> Passage of drug molecules across biological membranes.
>>Important for pharmacokinetic and pharmacodynamic features of drugs.
Processes of permeation:
(1) Does not make use of a carrier.
(2) Not saturable since it doesn’t bind to a specific carrier protein.
(3) Low structural specificity since it doesn’t require a carrier protein.
(4) Driven by concentration gradient .
Passive diffusion driven by concentration gradient.
(1) Passage through central pores in cell membranes
(2) Possible for low-molecular-weight substances (e.g., lithium, ethanol)
Aqueous diffusion via pores in cell membranes.
(1) Direct passage through the lipid bilayer
Facilitated by increased degree of lipid solubility
(2) Driven by a concentration gradient (nonionized forms move most easily)
(3) Lipid solubility is the most important limiting factor for drug permeation
A large number of lipid barriers separate body compartments.
(4) Lipid to aqueous partition coefficient (PC) determines how readily a drug molecule moves between lipid and aqueous media.
High lipid-to-oil PC favors lipid diffusion.
Most drugs are absorbed by passive diffusion.
>>Transporters are being identified and characterized that function in movement of molecules into (influx) or out (efflux) of tissues
>>Numerous transporters such as the ABC (ATP-binding cassette) family including P-glycoprotein or multidrug resistant-associated protein type 1 (MDR1) in the brain, testes, and other tissues play a role in excretion as well as in drug-resistant tumors.
Carrier-mediated transport is mediated by influx and efflux transporters.
Characteristics of carrier-mediated transport:
(1) Structural selectivity
(2) Competition by similar molecules
Drug competition at transporters is a site of drug-drug interactions.
(1) Energy-dependent transporters coupled to ATP hydrolysis (primary active transport); others take place by cotransport proteins (secondary active transport)
(2) Movement occurs against a concentration or electrochemical gradient
(3) Most rapid mode of membrane permeation
>>Sites of active transport:
(a) Neuronal membranes
(b) Choroid plexus
(c) Renal tubular cells
Active transport requires energy to move molecules against concentration gradient.
(1) Does not require energy from ATP hydrolysis
(2) Involves movement along a concentration or electrochemical gradient
Examples: include: movement of water soluble nutrients into cells:
(b) Amino acids
Sugars, amino acids, purines, pyrimidines and L-dopa by facilitated diffusion
>>Process in which a cell engulfs extracellular material within membrane vesicles
Used by exceptionally large molecules (molecular weight >1000), such as:
– Vitamin B12-intrinsic factor complex