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 kinetic 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 (Pd) of unbound drugs in rats and the partition coefficient (Papp) in an octanol:water system at pH 7.4 were estimated among acidic drugs. Using the values of unbound fraction (fS), the Pd values of the drugs were estimated from concentration-time profiles in serum and the peritoneal dialysate after intraperitoneal administration of drugs. The intrinsic membrane permeability (Pdm) was calculated based on a physiological pharmacokinetic model. The fS.Pdm values of thiopental and thiamylal (6.5 and 5.4 ml/min) were 2-3 times greater than the effective peritoneal 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 Pdm and log Papp. By considering the relationships, we estimated the Pdm of quinolonecarboxilic acids. The fS.Pdm values of quinolonecarboxilic acids were < 10% of the peritoneal effective blood flow rate, indicating that the peritoneal transport of quinolonecarboxilic acids was dominantly diffusion-limited because of low lipophilicity. In conclusion, there was a good correlation between log Pdm and log Papp. The prediction of Pdm can be useful to describe the peritoneal pharmacokinetics.
Nakashima
E
E
Hospital Pharmacy, Kanazawa University, Japan.
Matsushita
R
R
Ohshima
T
T
Tsuji
A
A
Ichimura
F
F
D000143:Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001798:Blood Proteins / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004058:Diffusion; D008297:Male; D008566:Membranes / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D010537:Peritoneum / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D000143:Acids; D001798:Blood Proteins