Effect of co-administration of cationic macromolecules on the in vivo disposition and in situ renal disposition characteristics of rhIL-11.
The effects of co-administration of cationic proteins on the in vivo disposition characteristics of recombinant human interleukin-11 (rhIL-11) in mice and on the renal disposition in the perfused rat kidney were investigated. Following a bolus intravenous injection of 10 microg/kg (111)In-labeled rhIL-11, along with cationic proteins at high dose (50 mg/kg), the plasma clearance of (111)In-labeled rhIL-11 was significantly decreased mainly due to a reduction in the hepatic clearance of (111)In-labeled rhIL-11. The effect on the renal clearance was relatively small, suggesting that the kidney has a high clearance capacity. The urinary excretion ratio increased by a factor of 2 or 4 with co-administration, suggesting that the cationic character of rhIL-11is involved in tubular re-absorption. An in situ renal disposition study supports these postulations. Thus, the renal and hepatic disposition of rhIL-11 is based on nonspecific cationic interaction. These data suggest that an efficient delivery system for this cytokine would require the reduction of electrostatic interaction of this molecule with these tissues in order to reduce the plasma clearance rate. These findings provide useful information for the construction of an rhIL-11 delivery system.
Takagi
Akira
A
Department of DDS Research, Novel Pharmaceutical Research Laboratories, Institute for Drug Development Research, Yamanouchi Pharmaceutical Co., Ltd., Shizuoka, Japan. takagi-a@yamanouchi.co.jp
Yabe
Yoshiyuki
Y
Oka
Yoshikazu
Y
Takakura
Yoshinobu
Y
Hashida
Mitsuru
M