Effect of albumin on artificial membrane permeation of acidic drugs

Background and purpose: The free fraction theory (FFT) plays a central role in pharmacokinetics and pharmacodynamics. However, for acidic drugs, deviations from FFT have been reported in cell‑based assays involving albumin binding. The purpose of the present study was to investigate the effect of albumin on the passive membrane permeation of acidic drugs in the parallel artificial membrane permeation assay (PAMPA). Experimental approach: Eight acidic drugs (atorvastatin, bosentan, entacapone, fluvastatin, meloxicam, pitavastatin, rosuvastatin, and tolbutamide) were used as model drugs. The PAMPA membrane consisted of phospholipids dissolved in decane. The effective permeation coefficient (Pe) was measured in the absence and presence of 4 % bovine serum albumin (BSA) in the donor solution. The unbound fraction (fu) was determined using equilibrium dialysis. Concentration dependence and phospholipid‑composition dependence of Pe were examined. Key results: Pe was substantially reduced by the addition of BSA, showing good consistency with FFT. The minor deviation from FFT was explained by a concentration‑dependent increase in the membrane permeability of unbound drug molecules, except for rosuvastatin. The effect of BSA on the permeability of rosuvastatin was influenced by phospholipid composition, possibly suggesting albumin-phospholipid interactions. Conclusion: PAMPA permeation showed good consistency with FFT. The slight deviations from FFT observed for the low‑permeability drugs can be explained by the concentration dependence of unbound drug permeability, except for rosuvastatin.