Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations

• Published in: Journal of the American Society of Nephrology Vol. 12; no. 5; pp. 1059 - 1071
• Main Authors: PODDER, Hemangshu, STEPKOWSKI, Stanislaw M, NAPOLI, Kimberly L, CLARK, James, VERANI, Regina R, CHOU, Ting-Chao, KAHAN, Barry D
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.05.2001
• Subjects: Animals; Biological and medical sciences; Body Weight - drug effects; Cholesterol - blood; Creatinine - blood; Cyclosporine - administration & dosage; Cyclosporine - pharmacokinetics; Cyclosporine - toxicity; Drug Interactions; Drug toxicity and drugs side effects treatment; Glomerular Filtration Rate - drug effects; Hematopoiesis - drug effects; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - toxicity; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Male; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Inbred WF; Sirolimus - administration & dosage; Sirolimus - pharmacokinetics; Sirolimus - toxicity; Tissue Distribution; Toxicity: urogenital system; Kidney disease; Drug combination; Urinary system disease; Glomerular filtration; Renal function; Pathophysiology; Rat; Sirolimus; Toxicity; Rodentia; Metabolic diseases; Lipids; Macrolide; Immunomodulator; Vertebrata; Mammalia; Treatment; Animal; Renal failure; Ciclosporin; Hyperlipemia; Dyslipemia
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.v1251059

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.