Investigation of the electrochemical oxidation products of zotepine and their fragmentation using on-line electrochemistry/electrospray ionization mass spectrometry.

When zotepine, an antipsychotic drug, was electrochemically oxidized using electrospray ionization mass spectrometry (ESI-MS) coupled with a microflow electrolytic cell, [M + 16 + H]+ (m/z 348), [M-H]+ (m/z 330) and [M-14 + H]+ (m/z 318) were observed as electrochemical oxidation product ions (M represents the zotepine molecule). Although a major fragment ion that was derived from the dimethyl aminoethyl moiety was observed only at m/z 72 in the collision-induced dissociation (CID) spectrum of zotepine, new fragments such as m/z 315 and 286 ions could be generated in the CID spectrum by combining electrochemical oxidation and CID. Since these fragments were relatively specific with high ion strength, it was thought that they would be useful for developing a sensitive LC-MS/MS assay. The S-oxide and N-demethylated products were detected by electrolysis assuring that a portion of P450 metabolites of zotepine could be mimicked by the electrochemistry/electrospray ionization mass spectrometry (EC/ESI-MS) system.

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.