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

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 omega-oxidized and beta-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 indicated the extensive inactivation of N-acetyl-leukotriene E4 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of Tc-99m Mebrofenin as a Clinical Probe to Assess Altered Hepatobiliary Transport: Integration of In Vitro, Pharmacokinetic Modeling, and Simulation Studies

“…Additionally, hepatotoxicants that are handled by the liver in a manner similar to MEB may cause significant toxicity in patients with obstructive cholestasis, where biliary excretion is impaired and a compensatory increase in hepatic egress occurs. Simulations of obstructive cholestasis revealed that liver exposure was increased 60% compared to normal subjects; these results are in accordance with changes in transit time through the liver that Guhlmann et al (19) observed for N-acetyl LTE 4 in rats with cholestasis due to bile duct obstruction.…”

“…The TR − rat strain has a hereditary mutation in the Abcc2 gene; like DubinJohnson patients, TR − rats exhibit impaired bilirubin excretion (due to the absence of canalicular Mrp2) and enhanced basolateral expression of Mrp3 (17,18). Consistent with these alterations in TR − rats, deficient biliary excretion of N-acetyl-leukotriene E 4 , an Mrp2 substrate, was compensated by leukotriene urinary excretion; interestingly, mean liver transit time was increased more than 3-fold in TR − compared to normal Wistar rats (19).…”

PET Tracers To Study Clinically Relevant Hepatic Transporters

“…21 This pioneering PET study showed how, in the case of impaired hepatic functionality (due to hereditary transporter deficiencies or bile duct obstruction), the extraction of leukotriene metabolites can be switched from hepatobiliary to renal clearance.…”

“…Also, drug metabolites 17,19 and endogenous compound derivatives 20,21 have been successfully labeled with 11 C and employed as PET tracers. Table 1 lists the PET tracers that have been used to study hepatic transporters.…”

“…73 In order to assess the contribution of different organs to the clearance of leukotrienes, a 11 C-labeled version of LTE 4 Nac, [ 11 C]-25, was prepared and its biodistribution was studied in normal rats, transporter-deficient mutant rats (with a hereditary defect in the leucotriene elimination), 74 and monkeys. 21 [ 11 C]-Acetyl chloride ([ 11 C]-24) was obtained by reaction of [ 11 C]-carbon dioxide with methylmagnesium chloride and subsequent treatment with phthaloyl chloride. The acetylation of LTE 4 was then performed in the presence of 2,6-dimethylpyridine to afford [ 11 C]-LTE 4 NAc ([ 11 C]-25) after HPLC purification (Scheme 10).…”