Efficacy of peritoneal dialysis of tolbutamide in rats under conditions of the plasma unbound fraction being increased.
Peritoneal dialysis of a highly protein-bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfamethoxazole treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfadimethoxine treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration-dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions.
Makita
Takashi
T
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Tsushima-Naka, Okayama 700-8530, Japan.
Aiba
Tetsuya
T
Izuwa
Yuki
Y
Komori
Yukiko
Y
Kawasaki
Hiromu
H
Kurosaki
Yuji
Y
D000465:Algorithms; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D015233:Models, Statistical; D010530:Peritoneal Dialysis; D010949:Plasma / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013412:Sulfadimethoxine / Q000493:pharmacokinetics; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics*
D000890:Anti-Infective Agents; D001798:Blood Proteins; D007004:Hypoglycemic Agents; D013412:Sulfadimethoxine; D014044:Tolbutamide