Lipid association increases the potency against primary medulloblastoma cells and systemic exposure of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats

• Published in: Pharmaceutical research 1999-06, Vol.16 (6), p.896-903
• Main Authors: BETHUNE, C, BLUM, A, GEYER, J. R, SILBER, J. R, HO, R. J. Y
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - pharmacology; Biological and medical sciences; Brain cancer; Cancer therapies; Cell Division - drug effects; Chemotherapy; Decomposition; Dimyristoylphosphatidylcholine; Drug Carriers; Drug Delivery Systems; Drug dosages; Drug Screening Assays, Antitumor; Drug Synergism; General aspects; General pharmacology; Lipids; Liposomes; Lomustine - administration & dosage; Lomustine - pharmacology; Male; Medical sciences; Medulloblastoma - drug therapy; Mortality; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phosphatidylglycerols; Physiology; Ratios; Rats; Rats, Wistar; Toxicity; Tumors
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1018886321917

To reduce the systemic toxicity and prolong the systemic presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized. The degree of CCNU association with lipid vesicles composed of 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-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. 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 microM, respectively, compared to 83+/-11.0 microM 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 microg x min/ml), and the terminal half-life (t1/2beta) 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. These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.