Dose-dependent pharmacokinetics and disposition of bisphosphonic prodrug of diclofenac based on osteotropic drug delivery system (ODDS).
Rat pharmacokinetics and in vivo disposition of a novel bisphosphonic prodrug of diclofenac (DIC-BP), synthesized with the aim of osteotropic delivery of diclofenac, were determined at whole body, organ and cellular levels in a dose range 0.32-10mg/kg. With an increase in injected dose, total body clearance was decreased while the distribution volume at steady state (V(dss)) was reduced and plasma half-life was prolonged. Over 50% of a dose of DIC-BP was selectively transported into osseous tissues after intravenous injection into rats at doses up to 1mg/kg. As dose increased, the skeletal distribution decreased with hepatic and splenic accumulations increasing. The intrahepatic distribution at 10mg/kg revealed that liver macrophages play a significant role in hepatic uptake of DIC-BP. This is consistent with general arguments that bisphosphonates themselves cannot distribute in soft tissues, but are taken up by the reticuloendothelial system as foreign substances when they form large complexes or aggregate with endogenous metals in plasma. Therefore, to optimize the osteotropic delivery of diclofenac via a bisphosphonic prodrug, the dosage regimen should be such that plasma concentration of DIC-BP is maintained at a level lower than that required for precipitate formation of complexes, similar to the usage of other bisphosphonates.
Hirabayashi
Hideki
H
Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Company, Osaka, Japan. hideki_hirabayashi@po.fujisawa.co.jp
Sawamoto
Taiji
T
Fujisaki
Jiro
J
Tokunaga
Yuji
Y
Kimura
Sumihisa
S
Hata
Takehisa
T
D000818:Animals; D004008:Diclofenac / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004164:Diphosphonates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004164:Diphosphonates; D011355:Prodrugs; D004008:Diclofenac