3.12
药物分布：血浆蛋白结合
药物主要附着在血浆蛋白上，只有一小部分保持非结合状态。未结合部分可以计算为一减去结合部分的比例。酸性药物通过可逆地结合到血浆白蛋白而形成大型非活性复合物，阻止它们通过生物屏障扩散。这些药物-蛋白质复合物起到药物的储库作用。随着非结合药物浓度的降低，这些复合物会迅速解离以释放出游离药物，保持非结合部分…
大多数药物主要与白蛋白等血浆蛋白结合，仅有小部分保持游离未结合状态。该游离未结合部分等于1减去结合部分的比例。
酸性药物可逆地与血浆白蛋白结合，形成大分子、无活性的复合物，无法扩散通过生物屏障。
此类药物-蛋白质复合物可作为药物储存库。当游离药物浓度下降时，复合物会迅速解离，释放出游离药物，从而维持游离药物的比例。
蛋白结合药物的量受游离药物浓度、蛋白浓度、结合位点数量以及药物与结合位点之间亲和力的影响。
不同的药物或内源性物质可竞争性地与血浆蛋白结合。
例如，磺胺类药物的竞争性结合会降低白蛋白对胆红素的亲和力，导致游离胆红素释放。这可能增加新生儿胆红素脑病的风险。
同样，在运动过程中，脂肪代谢会释放高浓度的游离脂肪酸进入血浆。这些脂肪酸会置换与白蛋白结合的药物，从而增加游离药物的浓度。
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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.