title: Increased cyclosporine bioavailability induced by experimental nephrotic syndrome in rats.
abstract: 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.
authors.affiliation: Departamento de Nefrologia, Hospital Infantil de México Federico Gómez, Dr. Marquez 162, Col. Doctores, Mexico, DF 06720, Mexico. maramedeiros@hotmail.com
authors.forename: Mara
authors.initials: M
authors.lastname: Medeiros
authors.forename: José
authors.initials: J
authors.lastname: Pérez-Urizar
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
authors.forename: Ricardo
authors.initials: R
authors.lastname: Muñoz-Arizpe
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castañeda-Hernández
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D011692:Puromycin Aminonucleoside; D016572:Cyclosporine; D002784:Cholesterol