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Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations
Hemangshu Podder1, Stanislaw M Stepkowski1, Kimberly L Napoli1
1Department of Surgery, Division of Immunology and Organ Transplantation, The University of Texas Medical School at Houston, Houston, Texas.
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.
Insights
Sirolimus (rapamycin) worsens cyclosporine-induced kidney dysfunction via pharmacokinetic interactions. Cyclosporine enhances sirolimus-induced myelosuppression and hyperlipidemia through pharmacodynamic effects, independent of pharmacokinetics.
Area of Science:
- Pharmacology
- Nephrology
- Toxicology
Background:
- Sirolimus (rapamycin; RAPA) and cyclosporine (CsA) are immunosuppressants with known toxicities.
- Understanding drug interactions is crucial for optimizing therapeutic use and minimizing adverse effects.
Purpose of the Study:
- To correlate the dynamic effects of RAPA and CsA, alone and in combination, on renal dysfunction, myelosuppression, and hyperlipidemia.
- To investigate the pharmacokinetic and pharmacodynamic interactions between RAPA and CsA.
Main Methods:
- Salt-depleted rats were treated with varying doses of RAPA and/or CsA for 14 days.
- Measurements included glomerular filtration rate (GFR), lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in blood and tissues.
- The median effect model was employed to analyze drug interactions.
Main Results:
- Monotherapy with high-dose RAPA or CsA reduced GFR.
- Combination therapy with lower doses of RAPA and CsA resulted in more pronounced GFR reduction.
- RAPA increased CsA concentrations, exacerbating renal dysfunction (pharmacokinetic interaction).
- CsA potentiated RAPA-induced myelosuppression and hyperlipidemia independently of pharmacokinetic interactions (pharmacodynamic interaction).
Conclusions:
- RAPA aggravates CsA-induced renal dysfunction through a pharmacokinetic interaction.
- CsA augments RAPA-induced myelosuppression and hyperlipidemia via a pharmacodynamic interaction.