Pharmacokinetics: is the fate of drugs within the body ,It involves drug :
1-Absorption
2-Distribution
3-Metabolism
4-Excretion
or it what hte body does to the drug
ADME:– Absorption, Distribution, Metabolism, Excretion.
Drug Permeation
>> Passage of drug molecules across biological membranes.
>>Important for pharmacokinetic and pharmacodynamic features of drugs.
Processes of permeation:
1/Passive diffusion
Characteristics:
(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.
**Aqueous diffusion:
(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.
**Lipid diffusion:
(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.
2/Carrier-mediated transport:
>>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.
(3) Saturable
**Active transport
(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
(d) Hepatocytes
Active transport requires energy to move molecules against concentration gradient.
**Facilitated diffusion
(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:
(a) Sugars
(b) Amino acids
(c) Purines
(d) Pyrimidines
Sugars, amino acids, purines, pyrimidines and L-dopa by facilitated diffusion
3/Pinocytosis/endocytosis/transcytosis
>>Process in which a cell engulfs extracellular material within membrane vesicles
Used by exceptionally large molecules (molecular weight >1000), such as:
-Iron-transferrin complex
– Vitamin B12-intrinsic factor complex
