Pharmacokinetic behaviour of cisplatin in peritoneal fluid after intraperitoneal administration of cisplatin-loaded microspheres.
The objective of this study was to establish a pharmacokinetic model for the estimation of unchanged cis-dichlorodiammine-platinum (II) (CDDP) concentration in peritoneal fluid after intraperitoneal administration of cisplatin-loaded microspheres (CDDP-MS) and to elucidate the accuracy of this model by comparisons between actual and simulated values after intraperitoneal administration of CDDP-MS. We developed a method enabling the precise and quick assessment of the drug concentration in the peritoneal cavity. The pharmacokinetic parameters obtained after intravenous bolus injection at a dose of 2 mg kg(-1) were total body clearance (1026 mL h(-1) kg(-1)), elimination rate constant (3.24 h(-1)) and distribution volume of systemic circulation (316.7 mL kg(-1)). After an intraperitoneal bolus injection at a dose of 5 mg kg(-1), the absorption rate constant from the peritoneal cavity (3.64 h(-1)) and the distribution volume of the peritoneal cavity (13.5 mL kg(-1)) were determined. The protein-binding rate constant in ascites was 0.58 h(-1). Using these pharmacokinetic parameters, we established a pharmacokinetic model consisting of two compartments. Administration of CDDP-MS at a dose of 10 mg kg(-1), which released CDDP over 7 days in-vitro, yielded sustained concentrations of unchanged CDDP (1-2 mg mL(-1)) in the peritoneal cavity that persisted for 7 days, and that were predictable by applying the in-vitro dissolution profile to the pharmacokinetic model. The findings obtained from this study are useful for understanding the basic pharmacokinetic characteristics of unchanged CDDP in the peritoneal cavity and may also be important in the development of optimized CDDP-MS formulations.
Tamura
T
T
DDS Research Department, Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd, Osaka, Japan. t-tamura@tanabe.co.jp
Imai
J
J
Matsukawa
Y
Y
Horikiri
Y
Y
Suzuki
T
T
Yoshino
H
H
Ike
O
O
D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001202:Ascitic Fluid / Q000378:metabolism; D001711:Biotransformation; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D008297:Male; D008863:Microspheres; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D002945:Cisplatin