QUANTITATIVE RELATIONSHIP BETWEEN STRUCTURE AND PERITONEAL MEMBRANE-TRANSPORT BASED ON PHYSIOLOGICAL PHARMACOKINETIC CONCEPTS FOR ACIDIC DRUGS

To describe quantitatively the peritoneal transport of drugs, the kine tic model, which involves changes in the volume and osmolality of the dialysate as well as the diffusion and convection of drugs across the peritoneum, was applied. The apparent peritoneal permeability (P-d) of unbound drugs in rats and the partition coefficient (P-app) in an oct anol:water system at pH 7.4 were estimated among acidic drugs, Using t he values of unbound fraction (f(s)), the P-d values of the drugs were estimated from concentration-time profiles in serum and the peritonea l dialysate after intraperitoneal administration of drugs, The intrins ic membrane permeability (P-dm) was calculated based on a physiologica l pharmacokinetic model. The f(s) . P-dm values of thiopental and thia mylal (6.5 and 5.4 ml/min) were 2-3 times greater than the effective p eritoneal blood flow, indicating that the peritoneal transport of the barbiturates with high lipophilicity was dominantly blood flow-limited . Evidence shows a high degree of correlation between log P-dm and log P-app. By considering the relationships, we estimated the P-dm of qui nolonecarboxilic acids, The f(s) . P-dm values of quinolonecarboxilic acids were <10% of the peritoneal effective blood flow rate, indicatin g that the peritoneal transport of quinolonecarboxilic acids was domin antly diffusion-limited because of low lipophilicity. In conclusion, t here was a good correlation between log P-dm and log P-app. The predic tion of P-dm can be useful to describe the peritoneal pharmacokinetics .