Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations Journal Article

Authors: Podder, H.; Stepkowski, S. M.; Napoli, K. L.; Clark, J.; Verani, R. R.; Chou, T. C.; Kahan, B. D.
Article Title: Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations
Abstract: This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml/min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol-occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.
Keywords: nephrotoxicity; kidney; rat; in-vivo; renal-transplant recipients; cyclosporine-a; whole-blood; acute rejection; sirolimus rapamycin; induced hypertension
Journal Title: Journal of the American Society of Nephrology
Volume: 12
Issue: 5
ISSN: 1046-6673
Publisher: American Society of Nephrology  
Date Published: 2001-05-01
Start Page: 1059
End Page: 1071
Language: English
ACCESSION: WOS:000168307600023
PUBMED: 11316866
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Ting-Chao Chou
    271 Chou