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Disposition and toxicity of amphotericin-B in the hyperlipidemic Zucker rat model
K Vadiei1, G Lopez-Berestein, D R Luke
1Department of Pharmaceutics, University of Houston, TX.
Abstract:
The pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function. Although triglyceride, cholesterol, HDL-cholesterol and LDL + VLDL-cholesterol levels were elevated in the obese compared with lean rats, protein: lipoprotein ratios were similar. There was a 2-fold increase in the area under the serum concentration-time curve of AmpB in obese rats compared to lean litter-mates (15,600 +/- 6900 v. 7800 +/- 2900 ng. h/ml; P less than 0.05); no differences in elimination rate constants were found between groups. Weight-corrected volume of distribution and total body clearance were significantly lower in obese compared with lean rats; no differences were found in absolute clearance or volume. Kidney levels of AmpB were markedly increased in obese versus lean rats. Similarly, kidney to serum ratios of AmpB were greater in obese compared with lean rats (152 +/- 113 v. 41 +/- 23; P less than 0.001). There was a significant decline in the creatinine clearance from baseline in the obese rats coupled with a rise in serum creatinine; no differences were found in lean rats. Similarities in absolute pharmacokinetic variables and protein: lipoprotein ratios suggest differences in AmpB disposition and toxicity are a result of differences in lipoprotein-mediated transport mechanisms between obese and lean rats.
Insights
Obese rats showed higher amphotericin-B (AmpB) levels and kidney accumulation, leading to toxicity. Lipoprotein differences likely explain altered AmpB pharmacokinetics in obesity.
Area of Science:
- Pharmacology
- Toxicology
- Obesity Research
Background:
- Lipophilic antifungal agents like amphotericin-B (AmpB) require careful dosing.
- Obesity can alter drug pharmacokinetics and toxicity.
- Hyperlipidemic obese rats serve as a model to study drug disposition in obesity.
Purpose of the Study:
- To investigate the pharmacokinetics and toxicity of amphotericin-B (AmpB) in hyperlipidemic obese rats.
- To compare AmpB disposition and renal effects in obese versus lean rats.
- To explore the role of lipoprotein differences in AmpB transport and toxicity.
Main Methods:
- Administered a single intravenous dose of AmpB (1.2 mg/kg) to obese and lean rats.
- Monitored serum AmpB concentrations over 36 hours.
- Assessed renal function through creatinine clearance and serum creatinine levels.
- Measured AmpB concentrations in kidney tissue.
Main Results:
- Obese rats exhibited a 2-fold increase in the area under the serum concentration-time curve for AmpB.
- Kidney levels and kidney-to-serum ratios of AmpB were significantly higher in obese rats.
- Obese rats showed a decline in creatinine clearance and a rise in serum creatinine, indicating nephrotoxicity.
- Weight-corrected volume of distribution and total body clearance were lower in obese rats.
Conclusions:
- Obesity significantly alters amphotericin-B pharmacokinetics, increasing exposure and kidney accumulation.
- Elevated AmpB levels and nephrotoxicity in obese rats are likely linked to altered lipoprotein-mediated transport.
- These findings highlight the need for dose adjustments and monitoring in obese patients receiving AmpB.