Distribution of [2-14C]merbarone in mice by autoradiography of whole-body cryosections.

The distribution of radiolabel in male mice was studied by autoradiography of whole-body cryosections at intervals during 24 h after i.v. injection (46.6 mg/kg) and during 4 h after oral administration (140 mg/kg) of [2-14C]merbarone. Following injection, radioactivity levels in the blood and highly vascular tissues declined to 8 h at which time only low levels were present in the systemic circulation. Only very low levels were seen in the brain and spinal cord at 0.5-3 min after dosing and levels were barely above background in autoradiograms obtained at 0.5-1 h. Radiolabel was concentrated in those regions which lack an effective blood-brain barrier particularly within the choroid plexuses. Radioactivity was rapidly taken up by the liver and kidneys and as the blood and body radioactivity levels decreased, these organs remained densely labeled. Significant biliary excretion had occurred by 30 min and the autoradiograms to 24 h showed radiolabeled compounds in the intestinal lumen. Between 1 and 8 h, the liver exhibited a stippled appearance as a result of labeling around branches of the portal vein due to enterohepatic recycling. The stippling was substantially diminished at 16 h. High levels of radioactivity were present in the kidney at 0.5-3 min after injection with both the kidney cortex and medulla initially densely labeled. At 4 h and thereafter, the radioactivity levels in the kidney were lower with most of the labeled compounds in the medulla. Accumulation in the liver and kidney was very low at 16-24 h after dosing and most of the merbarone dose had cleared from the body. Rapid absorption of merbarone occurred after oral administration with radiolabel first observed in the liver and kidney at 3-6 min after dosing. Peak levels in these organs and systemically were seen between 0.5 and 2 h. At 4 h, the radioactivity had largely cleared from the systemic circulation. The liver exhibited a stippled appearance soon after oral dosing similar to that observed following i.v. dosing affording evidence for enterohepatic recycling after i.v. administration. The relatively low systemic levels observed after oral dosing suggests that the liver binds much of the absorbed drug and its metabolites limiting the levels which reach the systemic circulation.