Fate of the predominant phospholipid component of DepoFoam drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats.
The distribution, metabolism, and excretion of dioleoylphosphatidylcholine (DOPC), the predominant phospholipid component of DepoFoam (DF) drug delivery matrix, was determined after lumbar intrathecal injection of double-radiolabeled ((14)CDOPC, (3)H-cytarabine) sustained-release encapsulated cytarabine (DF-cytarabine) in rats prepared with chronic spinal catheters. Radioactivity was quantitated in central nervous system (CNS) and peripheral tissues, cerebrospinal fluid (CSF), blood, urine, and feces at various time points up to 504 h. The distribution of (14)C radiolabel among lipid classes was also determined in selected body fluid samples. Both radiolabels distributed rapidly throughout the neuraxis after injection. Levels of both labels declined in a biphasic manner from CSF and plasma, with an initial rapid decline over the first 96 h, followed by a much slower rate of decline out to 504 h. Greater than 90% of the (3)H (drug) label was estimated to be excreted in urine. In contrast, the data suggest that most of the (14)C (phospholipid) label was expired as (14)CO(2); small percentages of the dose remained incorporated in CNS (7%) and peripheral tissues (8%) or were excreted in urine (6%). Characterization of lipidic (14)C in plasma confirmed metabolism of the parent lipid. The data confirm the sustained-release nature of the DF-cytarabine multivesicular liposomal preparation. Moreover, the results indicate that the DOPC lipid component enters standard catabolic path-ways after breakdown of the DF particles in the intrathecal space. Similar CSF and plasma kinetic profiles of drug and lipid radio-labels support the hypothesis that release of drug is related directly to breakdown of the lipid particles.
Kohn
F R
FR
Preclinical Development,DepoTech Corporation, San Diego, CA 92121, USA. fred_kohn@depotech.com
Malkmus
S A
SA
Brownson
E A
EA
Rossi
S S
SS
Yaksh
T L
TL