3.12
薬物の分布：血漿タンパク結合
薬物は主に血漿タンパク質に結合し、わずかな割合が非結合のままとなります。非結合部分は結合割合を１から引いた値で計算できます。酸性薬物は可逆的に血漿アルブミンに結合して大きな非活性複合体を形成し、生体障壁を通過することを防ぎます。これらの薬物-タンパク質複合体は薬物の貯蔵庫として機能します。非結合薬物…
ほとんどの薬物は主にアルブミンなどの血漿タンパク質に結合しており、結合していないのはごく一部です。この非束縛自由分数は、1 から束縛された分数を引いたものに等しくなります。
酸性薬物は、血漿アルブミンに可逆的に結合して、生物学的障壁を越えて拡散できない大きな不活性な複合体を形成します。
このような薬物-タンパク質複合体は、薬物貯蔵庫として機能します。遊離薬物の濃度が低下すると、複合体は急速に解離し、遊離薬物を放出し、遊離画分を維持します。
タンパク質結合薬物の量は、遊離薬物とタンパク質の濃度、結合部位の数、および薬物と結合部位との間の親和性によって影響を受けます。
異なる薬物または内因性物質が血漿タンパク質に競合的に結合する可能性があります。
例えば、スルホンアミドの競合的結合は、アルブミンのビリルビンに対する親和性を低下させ、遊離ビリルビンの放出を引き起こします。これにより、新生児のビリルビン脳症のリスクが高まる可能性があります。
同様に、運動中、脂肪代謝は高濃度の遊離脂肪酸を血漿中に放出します。これらの脂肪酸は、アルブミンに結合した薬物を置換し、遊離薬物の濃度を高めます。
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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.