Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein

Abstract

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

Statins and osteoporosis: new role for old drugs

“…Site-specific drug delivery via a pro-drug approach has generated considerable interest for enhancing the potency or diminishing the side effects of a drug. Recently, there have been many reports of targeting drugs to osseous tissue by conjugating them with osteotropic moieties, like bisphopshonates (Fujisaki et al 1995(Fujisaki et al , 1996(Fujisaki et al , 1997(Fujisaki et al , 1998Hirabayashi et al 2001). The drug is linked to a bisphosphonic moiety via bioreversible bonds.…”

Bisphosphonates: therapeutics potential and recent advances in drug delivery

“…Fujisaki and coworkers recently proposed an osteotropic DDS based on a bisphosphonic prodrug concept as a novel method for site specific and controlled delivery of other drugs to the bone. This approach is based on the chemical adsorption of the prodrug to the mineral component, HA, in the bone through the bisphosphonic promoiety (Fujisaki et al, 1996).…”

Bisphosphonate Prodrugs

“…The potential of BPs to serve as carriers for bone-specific delivery was already pointed out by Fleisch over 15 years ago [66]. More recently, the concept of ODDS which makes targeted delivery of drugs to the bone or bone marrow possible, have been developed [45][46][47][48][49][50][51][52].…”

“…The first approach is based on a targeted carrier system that is activated by dipeptide prodrugs [27][28][29][30], while in the second method low log P app values are made to increase by masking one or more of the ionizable groups [31][32][33][34][35][36][37][38][39][40][41][42][43][44]. The third system, called the Ostetropic Drug Delivery System (ODDS), makes possible the targeted delivery of drugs to the bone or bone marrow [45][46][47][48][49][50][51][52].…”