Pharmacokinetics of nitroxide NMR contrast agents.

Pharmacokinetics of the nitroxide stable free radical functionality of compounds containing this moiety were evaluated in the rat. The agents were injected i.v. at either high (1.75 mmoles/kg) or low (10 mumoles/kg) dose, and timed blood samples were drawn and assayed for nitroxide concentration by EPR spectrometry. Similarly, various organs and tissues were removed at specified times after injection and homogenized for determination of nitroxide concentration. Urine was collected by catheter for estimation of urinary excretion of the intact nitroxide free radical. At high doses, the various nitroxides exhibited an initial rapid disposition phase, followed by a terminal disposition phase with disappearance from the blood showing apparent log-linear half-lives of about 5 to 30 minutes. Generally, 20 to 60% of the dose was recovered in the urine. At low doses, dissimilar results were obtained. Blood levels again showed biphasic decay; however, blood concentrations at all times were much lower than those predicted by the high dose kinetics, indicating probably nonlinear pharmacokinetic behavior. Tissue homogenate studies showed low or nondetectable levels of nitroxide signal, demonstrating that the low blood concentrations could not be accounted for by a rapid uptake into specific tissues. Moreover, only 2 to 6% of the nitroxide could be recovered in the urine. Additional studies demonstrated that at the low dose a rapid in vivo bioreduction occurred which appeared to be saturable at the higher dose.