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Noninvasive assessment of hepatobiliary and renal elimination of cysteinyl leukotrienes by positron emission tomography

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Abstract

N-Acetyl-leukotriene E4 has been identified as an endogenous, biologically less active cysteinyl leukotriene metabolite in rodents and humans. To evaluate the ratio of hepatobiliary to renal elimination of leukotrienes noninvasively by positron emission tomography (PET), we synthesized N-[11C]acetyl-leukotriene E4 by chemical N-acetylation of leukotriene E4. After the intravenous injection of N-[11C]acetyl-leukotriene E4 in normal rats and monkey, uptake by the liver and subsequent excretion into bile were largely responsible for its rapid elimination from blood. In the Cynomolgus monkey, renal excretion of the leukotriene into urine was of additional quantitative importance. Kinetic modeling indicated a mean transit time through the liver of 17 minutes and 34 minutes in rat and monkey, respectively; the corresponding hepatic excretion half-times amounted to 8.5 minutes and 16 minutes. In a mutant rat strain deficient in the hepatobiliary excretion of cysteinyl 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. After transport from the liver back into the circulating blood of ω-oxidized and β-oxidized metabolites of N-[11C]acetyl-leukotriene E4, renal excretion compensated for the impairment of hepatobiliary elimination in the transport mutant. Metabolite analyses in urine after intravenous injection of N-[3H]acetyl-leukotriene E4 indicáted the extensive inactivation of N-acetyl-leukotriene E4 by β-oxidation from the ω-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-[11C]Acetyl-leukotriene E4 enables the assessment of hepatobiliary function by PET as well as the quantitative and noninvasive evaluation of the contribution of liver and kidney to leukotriene elimination under normal and various pathophysiological conditions.

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