Pharmacokinetics of prolonged-release CPT-11-loaded microspheres in rats.

CPT-11-containing microspheres composed of poly-D,L-lactic acid or poly (D,L-lactic acid-co-glycolic acid) copolymers were prepared by an oil-in-water evaporation method. The size and shape of the microspheres were examined, and the drug release rates were analyzed from the in vitro release profiles. CPT-11 aqueous solution was intravenously or intraperitoneally injected at 10 mg/kg, and microspheres were intraperitoneally administered at 50 mg eq CPT-11/kg in rats. The microspheres had an average diameter of around 10 microm and their shape was spherical. All the microspheres contained CPT-11 in a lactone form, and their drug contents and release profiles were basically similar to those of previous microspheres. After i.v. injection of CPT-11 solution, the CPT-11 plasma concentration decreased quickly, SN-38 decreased slowly at a much lower level, and SN-38 glucuronide (SN-38G) declined very slowly at a higher level than SN-38. The plasma concentration of CPT-11 reached a maximum at 30 min after i.p. administration of CPT-11 solution. The area under the plasma concentration-time curve (AUC) of CPT-11 after i.p. administration was somewhat lower compared with that after i.v. administration, but the plasma concentration-time profiles of SN-38 and SN-38G were nearly identical between i.v. and i.p. administration. An i.p. administration of the microspheres resulted in gradually increasing or almost constant CPT-11 levels. The levels of SN-38 were also stable during the observation period (4 days) except for the slowest releasing microsphere in which SN-38 was not detected after 24 h following administration. Intraperitoneal administration of any of the microspheres resulted in stable and similar levels of SN-38G after 24 h following administration. When judging from apparent simple pharmacokinetic analysis, an inconsistency was found between the in vitro drug release and the plasma level to a fair extent, but overall the in vivo drug release rate from microspheres was considered parallel to the in vitro one. The microspheres showing a faster release of CPT-11 exhibited higher plasma levels of CPT-11 and SN-38, explaining the previous results that efficacy was better when the in vitro release rate was higher. That the SN-38 level could be attained to a certain extent even at the range of modest or low plasma concentration of CPT-11 in each administration may be related to the non-linear metabolic conversion from CPT-11 to SN-38.