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.

Pharmacokinetics of cyclosporin - a microemulsion in children with idiopathic nephrotic syndrome

“…This study also observed a positive correlation of AUC 0–12 with cholesterol levels and negative correlations with CSA clearance and with its distribution volume (13). However, it is important to note that this was an experimental study conducted under ideal conditions; therefore, the findings cannot be directly applied to clinical practice (13). …”

“…In addition, it is unclear whether abnormalities observed during relapse of the NS are able to interfere with its CSA-PK or if the abnormalities could influence the drug prescription (13). Some studies have suggested that edema, hypoproteinemia, and hypercholesterolemia are involved in CSA bioavailability and clearance (13,16).…”

“…Some studies have suggested that edema, hypoproteinemia, and hypercholesterolemia are involved in CSA bioavailability and clearance (13,16). Hypercholesterolemia is particularly important in CSA-PK because the drug is highly lipophilic and binds to blood cells and plasma proteins; the relative distribution depends on the temperature, drug concentration, hematocrit, and plasma lipoproteins (23).…”

“…It is well known that the CSA has a narrow therapeutic window (13,14). In clinical practice, the pharmacokinetic (PK) profile can provide an indicator of the appropriate CSA dose to obtain an efficient effect and to try to avoid adverse events (15).…”

“…If this is so, then different TDM might be necessary during each of these periods. Furthermore, it is important to find a drug that is effective and safe (13,16). …”