IN-VIVO PHARMACOKINETICS OF NITROXIDES IN MICE

The in vivo reduction kinetics of twenty different nitroxide compounds in mice has been investigated by using an electron paramagnetic reson ance (EPR) spectrometer, equipped with an S-band loop-gap resonator, o perating at 3.5 GHz. The diameter of the resonator (4 mm) fits well th e tip of the mouse tail, thus allowing the direct detection of in vivo free radicals in the blood circulation. After intravenous injection, the nitroxide signal in the circulation of the mouse tail was followed with time; no anesthetic agent was used. For the pyrrolidine nitroxid es (five-member rings) with different functional groups, the t(1/2) va lues followed the order: = O > COO- > OH > CONH2 approximate to CH2NH2 > NH2. A different trend was obtained for the piperidine nitroxides ( six-member rings): COO- > CH2NH2 > OH approximate to NH2 > CONH2 > = O . The most striking observation was that while the t(1/2) value of the carbonyl pyrrolidine is the longest among all the nitroxides tested f or this property, that of the carbonyl piperidine is the shortest. Com parison of the in vivo decay kinetics of six pairs of pyrrolidine nitr oxides and piperidine nitroxides with same functional groups showed th at the t(1/2) values of the former are 2 to 28 times longer than the l atter. It is concluded here that the pyrrolidine nitroxides are more r esistant to cellular metabolism in vivo when compared to the piperidin e nitroxides. (C) Academic Press, Inc.