3.12
Arzneimittelverteilung: Plasmaproteinbindung
Arzneimittel binden überwiegend an Plasmaproteine, wobei nur ein kleiner Prozentsatz ungebunden bleibt. Der ungebundene Teil kann als Eins minus dem g…
Die meisten Medikamente sind primär an Plasmaproteine wie Albumin gebunden, wobei nur ein kleiner Teil ungebunden bleibt. Dieser ungebundene freie Bruch ist gleich eins minus dem Bruch, der gebunden ist.
Saure Medikamente binden reversibel an Plasmaalbumin und bilden große, inaktive Komplexe, die nicht in der Lage sind, biologische Barrieren zu überwinden.
Solche Wirkstoff-Protein-Komplexe dienen als Wirkstoff-Reservoire. Wenn die Konzentration der freien Arzneimittel abnimmt, dissoziieren die Komplexe schnell, wodurch das freie Arzneimittel freigesetzt und die freie Fraktion erhalten bleibt.
Die Menge an proteingebundenen Arzneimitteln wird durch die Konzentration des freien Arzneimittels und Proteins, die Anzahl der Bindungsstellen und die Affinität zwischen dem Arzneimittel und den Bindungsstellen beeinflusst.
Unterschiedliche Medikamente oder körpereigene Substanzen können kompetitiv an Plasmaproteine binden.
Zum Beispiel verringert die kompetitive Bindung von Sulfonamid die Affinität von Albumin zu Bilirubin, was zur Freisetzung von freiem Bilirubin führt. Dies kann das Risiko einer Bilirubin-Enzephalopathie bei Neugeborenen erhöhen.
In ähnlicher Weise setzt der Fettstoffwechsel während des Trainings hohe Konzentrationen an freien Fettsäuren an das Plasma frei. Diese Fettsäuren verdrängen die an Albumin gebundenen Medikamente und erhöhen die Konzentration an freien Medikamenten.
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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.