3.12
Distribution des médicaments : liaison aux protéines plasmatiques
Les médicaments se lient principalement aux protéines plasmatiques, avec seulement un faible pourcentage restant libre. La partie libre peut être calc…
La plupart des médicaments sont principalement liés aux protéines plasmatiques telles que l’albumine, seule une petite fraction restant non liée. Cette fraction libre non liée est égale à un moins la fraction liée.
Les médicaments acides se lient de manière réversible à l’albumine plasmatique pour former de grands complexes inactifs qui sont incapables de se diffuser à travers les barrières biologiques.
De tels complexes médicament-protéine servent de réservoirs de médicaments. Lorsque la concentration de drogues libres diminue, les complexes se dissocient rapidement, libérant la drogue libre et maintenant la fraction libre.
La quantité de médicaments liés aux protéines est influencée par la concentration de médicament libre et de protéine, le nombre de sites de liaison et l’affinité entre le médicament et les sites de liaison.
Différents médicaments ou substances endogènes peuvent se lier de manière compétitive aux protéines plasmatiques.
Par exemple, la liaison compétitive du sulfamide réduit l'affinité de l'albumine pour la bilirubine, provoquant la libération de bilirubine libre. Cela peut augmenter le risque d’encéphalopathie bilirubinique chez les nouveau-nés.
De même, pendant l’exercice, le métabolisme des graisses libère de fortes concentrations d’acides gras libres dans le plasma. Ces acides gras déplacent les médicaments liés à l’albumine et augmentent la concentration des médicaments libres.
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Q1: What fraction of drugs remains unbound in plasma?
Only a small fraction of drugs remains unbound in plasma, while most bind to plasma proteins like albumin. The unbound free fraction equals one minus the fraction that is bound. This free fraction is pharmacologically active and capable of producing drug effects and crossing biological barriers to reach target tissues.
Q2: How do drug-protein complexes function as drug reservoirs?
Acidic drugs reversibly bind to plasma albumin, forming large inactive complexes that cannot diffuse across biological barriers. When free drug concentration declines, these complexes rapidly dissociate to release free drug, maintaining the unbound fraction. This reservoir mechanism helps sustain drug availability and therapeutic effects throughout the body.
Q3: What factors determine the amount of protein-bound drug?
Protein-bound drug quantity depends on the concentration of free drug and protein, the number of available binding sites, and the affinity between drug and binding sites. These factors work together to establish equilibrium between bound and unbound drug states, influencing overall drug distribution and pharmacological activity.
Q4: How does competitive binding affect drug and bilirubin levels?
Different drugs and endogenous substances compete for plasma protein binding sites. When sulfonamide competitively binds to albumin, it reduces albumin's affinity for bilirubin, causing free bilirubin release. This increases bilirubin encephalopathy risk in newborns by elevating unbound bilirubin concentrations in the bloodstream.
Q5: What happens to drug-protein binding during exercise?
During exercise, fat metabolism releases high concentrations of free fatty acids into plasma. These fatty acids displace drugs bound to albumin through competitive binding, increasing the concentration of free, unbound drugs. This displacement can enhance drug bioavailability and potentially alter therapeutic effects and drug efficacy.
Q6: Why are acidic drugs unable to cross biological barriers when protein-bound?
Acidic drugs form large, inactive complexes when reversibly bound to plasma albumin. These complexes are too large and polar to diffuse across biological membranes, effectively sequestering the drug in the vascular compartment. Only the unbound free fraction can penetrate tissues and exert pharmacological effects at target sites.
Q7: How does the unbound drug fraction relate to drug efficacy?
Only the unbound free fraction of drug is pharmacologically active and capable of producing therapeutic effects. The unbound fraction is calculated as one minus the bound fraction. Changes in protein binding through competitive displacement or altered protein concentrations directly affect drug efficacy, clinical outcomes, and therapeutic success.