Pharmacokinetics in the rat and the dog of a nonionic nitroxide contrast agent for magnetic resonance imaging.

Nitroxides are paramagnetic stable free radicals that have demonstrated effectiveness as contrast agents in proton magnetic resonance imaging (MRI). The pharmacokinetics and metabolic fate, determinants of the time course of MRI contrast enhancement, of a new nonionic pyrrolidine nitroxide derivative, TAP (2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carbonic acid-(2,3-dihydroxy-1-hydroxymethyl)-amide), were evaluated in the rat and the dog. A biexponential decline of the blood concentration of TAP was observed in both species after intravenous administration of 0.1- and 2.5-mmol/kg doses. The clearances in the rat, estimated after the low and high doses (15.4 +/- 2.0 and 15.3 +/- 1.4 mL/min.kg, respectively), were about twofold higher than those observed in two beagles (7.4 and 7.1 mL/min.kg for Dog #1 and 6.3 and 6.0 mL/min.kg for Dog #2). The hydroxylamine of TAP, formed by a one-electron reduction of the nitroxide moiety, was the only metabolite observed. This bioreduction of TAP has implications for its use as a MRI contrast agent because the diamagnetic hydroxylamine lacks contrast enhancing activity. In both animal species, the urinary recoveries of the dose as unchanged TAP and its hydroxylamine were essentially complete for the 24-h urine collections (92 to 98% and 83 to 95% for the rats and the dogs, respectively). Anticipated conjugative metabolism of the hydroxyl-containing side chain of TAP was not observed. Renal excretion of unchanged TAP was the predominant route of elimination, as renal clearance was estimated to be between 47 and 89% of total clearance in the dogs. Bioreduction in vivo was slower than that expected from the observed reduction of TAP in vitro in ascorbic acid solution and in rat liver and kidney homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)