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.
Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
C
C
Bethune
A
A
Blum
J R
JR
Geyer
J R
JR
Silber
R J
RJ
Ho
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