Increased cyclosporine bioavailability induced by experimental nephrotic syndrome in rats.
Components of whole blood and plasma are highly altered during the presentation of nephrotic syndrome. The present study was aimed to explore the influence of nephrotic syndrome on the pharmacokinetics of cyclosporine (CsA) (10 mg/kg) administered i.v. to control or puromycin-induced nephrotic rats (P-NS). We found an increase in CsA bioavailability in the nephrotic group compared with controls. The area under the curve of blood CsA versus time (AUCiv) increased from 27.7 +/- 5.3 to 60.6 +/- 13.8 mug.h.mL-1 in control and P-NS rats, respectively. The AUCiv augmentation was positively correlated with cholesterol levels. On the other hand, the total body clearance was significantly lower (0.38 +/- 0.06 vs. 0.17 +/- 0.03 L.(kg body mass)-1.h-1) and the volume of distribution at steady state (3.70 +/- 0.52 vs. 2.85 +/- 0.32 L/kg) was significantly smaller in nephrotic rats as compared with control. These pharmacokinetic changes lead to a longer terminal half-life of CsA in P-NS rats (11.8 +/- 1.6 vs. 6.9 +/- 0.91 h). We conclude that the physiopathologic changes induced by the nephrotic syndrome in P-NS animals result in a significant increase in CsA blood exposure by both the decrease in drug distribution and the reduction in elimination rate of CsA.
Medeiros
Mara
M
Departamento de Nefrologia, Hospital Infantil de México Federico Gómez, Dr. Marquez 162, Col. Doctores, Mexico, DF 06720, Mexico. maramedeiros@hotmail.com
Pérez-Urizar
José
J
Pedraza-Chaverri
José
J
Muñoz-Arizpe
Ricardo
R
Castañeda-Hernández
Gilberto
G
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D006207:Half-Life; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000378:metabolism; D034141:Hypoalbuminemia / Q000139:chemically induced / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000378:metabolism*; D011692:Puromycin Aminonucleoside / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D007166:Immunosuppressive Agents; D011692:Puromycin Aminonucleoside; D016572:Cyclosporine; D002784:Cholesterol