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


METHODS
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.


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 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.


CONCLUSIONS
These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.
Bethune
C
C
Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
Blum
A
A
Geyer
J R
JR
Silber
J R
JR
Ho
R J
RJ
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004134:Dimyristoylphosphatidylcholine; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D008081:Liposomes; D008130:Lomustine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy*; D010715:Phosphatidylglycerols; D051381:Rats; D017208:Rats, Wistar
D018906:Antineoplastic Agents, Alkylating; D004337:Drug Carriers; D008081:Liposomes; D010715:Phosphatidylglycerols; D008130:Lomustine; C002773:dimyristoylphosphatidylglycerol; D004134:Dimyristoylphosphatidylcholine