Utility of 99mTc-mebrofenin for assessing cytokine-dependent liver inflammation

617 Objectives: Hepatic handling of 99mTc-mebrofenin is altered in the presence of inflammatory cytokines (J Nucl Med.2005;46:148-152). The objective of this study was to determine whether the hepatic clearance of 99mTc-mebrofenin is useful for assessing liver inflammation associated with inflammatory cytokines. Methods: Thirty six F344 rats weighing 120-160g were used. Rats were divided into 6 groups of 6 animals each as follows: 1 control group and 5 experimental groups. To induce discrete, acute liver injury, rats were given a single intramuscular injection of carbon tetrachloride (CCl4), ranging from 0.25 to 1 ml/kg. The animals were studied for up to 4 weeks following CCl4 injection. The onset of liver injury was determined by measuring serum alanine aminotransferase (ALT) and by histological grading of inflammatory activity. Nine additional animals were treated with the inflammatory cytokines, IL-6 and TNF-α, either alone or in combination, in single doses ranging from 6 ng/kg to 6 μg/kg. To determine 99mTc-mebrofenin clearance, animals received 7.4 MBq of 99mTc-mebrofenin followed by dynamic imaging at 10 sec/frame for 60 min, using a 64 x 64 x 16 matrix and a zoom factor of 2. Data analysis used the Pegasys system. Regions of interest were drawn over the liver and hepatic time-activity curves were generated. Percent retention of peak hepatic 99mTc-mebrofenin activity at 60 minutes post injection was determined. Results: In untreated control rats, 24±2% of peak hepatic 99mTc-mebrofenin activity was retained at 60 minutes. Within 24 hours following administration of even the lowest dose of CCl4, 99mTc-mebrofenin excretion was markedly impaired, with 95±2% mebrofenin activity retained at 60 minutes, p Conclusions: Hepatic inflammation altered 99mTc-mebrofenin transporter activity for an extended period. This was mediated by the inflammatory cytokines, IL-6 and TNF-α, which regulate hepatobiliary transporters. These data suggest that 99mTc-mebrofenin may be a useful tracer for noninvasive assessment of liver inflammation. Research Support (if any): This investigation was funded in part by NIH RO1 DK-46952 and P30 DK-41296 grants.