Abstract
Purpose. To reduce the systemic toxicity and prolong the systemic presence of l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized.
Methods. The degree of CCNU association with lipid vesicles composed of 1,2-dimyristoyl-sn- glycero-3-phosphocholine (DMPC) and l,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and the drug decomposition rates of lipid-drug complexes were monitored. Effects of lipid association on drug potency against medulloblastoma cells and total systemic drug exposure in rats were determined.
Results. At a CCNU:lipid molar ratio greater than 1:5, more than 90% of the drug was associated with the lipid vesicles. In aqueous suspensions, lipid association significantly reduced the first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited a 4-fold increase in drug sensitivity with medulloblastoma cells. IC50 values for CCNU admixed and encapsulated with lipid vesicles were 18 ± 4.9 and 14.0 ± 2.2 μM, respectively, compared to 83 ± 11.0 μM for free CCNU. When administered to rats, lipid-associated CCNU increased the AUC (area under the concentration-time curve) of CCNU by approximately 2-fold (20.46 ± 2.15 compared to 39.59 ±1.87 μg⋅min/ml), and the terminal half-life (t1/2β) by almost 9-fold (17 ± 9 compared to 147 ± 48 min) over free CCNU. Despite the increase in total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a significantly lower frequency of acute neurotoxicity.
Conclusions. These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.
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Bethune, C., Blum, A., Geyer, J.R. et al. Lipid Association Increases the Potency Against Primary Medulloblastoma Cells and Systemic Exposure of l-(2-Chloroethyl)-3-Cyclohexyl-1-Nitrosourea (CCNU) in Rats. Pharm Res 16, 896–903 (1999). https://doi.org/10.1023/A:1018886321917
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DOI: https://doi.org/10.1023/A:1018886321917