NONINVASIVE ASSESSMENT OF HEPATOBILIARY AND RENAL ELIMINATION OF CYSTEINYL LEUKOTRIENES BY POSITRON EMISSION TOMOGRAPHY

N-Acetyl-leukotriene E(4) has been identified as an endogenous, biolog ically less active cysteinyl leukotriene metabolite in rodents and hum ans. To evaluate the ratio of hepatobiliary to renal elimination of le ukotrienes noninvasively by positron emission tomography (PET), we syn thesized N-[C-11]acetyl-leukotriene E(4) by chemical N-acetylation of leukotriene E(4). After the intravenous injection of N-[C-11]acetyl-le ukotriene E(4) in normal rats and monkey, uptake by the liver and subs equent excretion into bile were largely responsible for its rapid elim ination from blood. In the Cynomolgus monkey, renal excretion of the l eukotriene into urine was of additional quantitative importance. Kinet ic modeling indicated a mean transit time through the liver of 17 minu tes and 34 minutes in rat and monkey, respectively; the corresponding hepatic excretion half-times amounted to 8.5 minutes and 16 minutes. I n a mutant rat strain deficient in the hepatobiliary excretion of cyst einyl leukotrienes across the canalicular membrane, the apparent mean liver transit time was 54 minutes, and the hepatic excretion half-time was 29 minutes, indicating prolonged organ storage and metabolism. Af ter transport from the Liver back into the circulating blood of omega- oxidized and beta-oxidized metabolites of N-[C-11]acetyl-leukotriene E (4), renal excretion compensated for the impairment of hepatobiliary e limination in the transport mutant. Metabolite analyses in urine after intravenous injection of N-[H-3]acetyl-leukotriene E(4) indicated the extensive inactivation of N-acetyl-leukotriene E(4) by beta-oxidation from the omega-end in the mutants. A similar shift from hepatobiliary to renal cysteinyl leukotriene elimination was monitored in rats with cholestasis due to bile duct obstruction. N-[C-11]Acetyl-leukotriene E(4) enables the assessment of hepatobiliary function by PET as well a s the quantitative and noninvasive evaluation of the contribution of l iver and kidney to leukotriene elimination under normal and various pa thophysiological conditions.