Advertisement

Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography

Published:February 26, 2017DOI:https://doi.org/10.1016/j.jhep.2017.02.023

      Background & Aims

      Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET).

      Methods

      Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar.

      Results

      Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20–1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13–0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30–0.62) min−1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005–0.07 min−1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006–0.27) min−1, 2.3 times higher than the rate constant for backflux to blood (0.05, 0.04–0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6–3.1) min in healthy participants and 6.4 (3.1–23.7) min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023–0.11) min−1 in healthy participants and only slightly reduced in patients 0.039 (0.017–0.066).

      Conclusions

      This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease.

      Lay summary

      Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions.
      Clinical trial registration number: The trial is registered at ClinicalTrials.gov (NCT01879735).

      Graphical abstract

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kullak-Ublick G.A.
        • Stieger B.
        • Meier P.J.
        Enterohepatic bile salt transporters in normal physiology and liver disease.
        Gastroenterology. 2004; 126: 322-342
        • Trauner M.
        • Boyer J.L.
        Bile salt transporters: molecular characterization, function, and regulation.
        Physiol Rev. 2003; 83: 633-671
        • Hofmann A.F.
        The enterohepatic circulation of bile acids in man.
        Clin Gastroenterol. 1977; 6: 3-24
        • Hofmann A.F.
        Chemistry and enterohepatic circulation of bile acids.
        Hepatology. 1984; 4: 4S-14S
        • Hylemon P.B.
        • Zhou H.
        • Pandak W.M.
        • Ren S.
        • Gil G.
        • Dent P.
        Bile acids as regulatory molecules.
        J Lipid Res. 2009; 50: 1509-1520
        • Noe J.
        • Stieger B.
        • Meier P.J.
        Functional expression of the canalicular bile salt export pump of human liver.
        Gastroenterology. 2002; 123: 1659-1666
        • Wagner M.
        • Zollner G.
        • Trauner M.
        New molecular insights into the mechanisms of cholestasis.
        J Hepatol. 2009; 51: 565-580
        • Sørensen M.
        • Munk O.L.
        • Ørntoft N.W.
        • Frisch K.
        • Andersen K.J.
        • Mortensen F.V.
        • et al.
        Hepatobiliary secretion kinetics of conjugated bile acids measured in pigs by 11C-cholylsarcosine PET.
        J Nucl Med. 2016; 57: 961-966
        • Frisch K.
        • Jakobsen S.
        • Sørensen M.
        • Munk O.L.
        • Alstrup A.K.
        • Ott P.
        • et al.
        [N-methyl-11C]cholylsarcosine, a novel bile acid tracer for PET/CT of hepatic excretory function: radiosynthesis and proof-of-concept studies in pigs.
        J Nucl Med. 2012; 53: 772-778
        • Winkler K.
        • Tygstrup N.
        Determination of hepatic blood flow in man by cardio green.
        Scand J Clin Lab Invest. 1960; 12: 353-356
        • Skak C.
        • Keiding S.
        Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man.
        Liver. 1987; 7: 155-162
        • Leggett R.W.
        • Williams L.R.
        Suggested reference values for regional blood volumes in humans.
        Health Phys. 1991; 60: 139-154
        • Hwang S.
        • Lee S.G.
        • Kim K.H.
        • Park K.M.
        • Ahn C.S.
        • Moon D.B.
        • et al.
        Correlation of blood-free graft weight and volumetric graft volume by an analysis of blood content in living donor liver grafts.
        Transplant Proc. 2002; 34: 3293-3294
        • Lassen N.A.
        • Crone C.
        The extraction fraction of a capillary bed to hydrophilic molecules: theoretical considerations regarding the single injection technique with a discussion of the role of diffusion between laminar streams (Taylor’s effect).
        in: Crone C. Lassen N.A. Capillary permeability. Munksgaard, Copenhagen1970: 48-59
        • Crone C.
        The permeability of capillaries in various organs as determined by use of the ‘indicator diffusion’ method.
        Acta Physiol Scand. 1963; 58: 292-305
        • Bass L.
        • Keiding S.
        • Winkler K.
        • Tygstrup N.
        Enzymatic elimination of substrates flowing through the intact liver.
        J Theor Biol. 1976; 61: 393-409
        • Winkler K.
        • Bass L.
        • Keiding S.
        • Tygstrup N.
        The physiologic basis for clearance measurements in hepatology.
        Scand J Gastroenterol. 1979; 14: 439-448
        • Ott P.
        • Keiding S.
        • Johnsen A.H.
        • Bass L.
        Hepatic removal of two fractions of indocyanine green after bolus injection in anesthetized pigs.
        Am J Physiol. 1994; 266: G1108-G1122
        • Bosch J.
        Vascular deterioration in cirrhosis: the big picture.
        J Clin Gastroenterol. 2007; 41: S247-S253
        • Jazrawi R.P.
        • de Caestecker J.S.
        • Goggin P.M.
        • Britten A.J.
        • Joseph A.E.
        • Maxwell J.D.
        • et al.
        Kinetics of hepatic bile acid handling in cholestatic liver disease: effect of ursodeoxycholic acid.
        Gastroenterology. 1994; 106: 134-142
        • Boyer J.L.
        • Bloomer J.R.
        Canalicular bile secretion in man. Studies utilizing the biliary clearance of (14C)mannitol.
        J Clin Invest. 1974; 54: 773-781
        • Munk O.L.
        • Keiding S.
        • Bass L.
        Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation.
        Am J Physiol Gastrointest Liver Physiol. 2003; 285: G671-G680
        • Schmassmann A.
        • Angellotti M.A.
        • Ton-Nu H.T.
        • Schteingart C.D.
        • Marcus S.N.
        • Rossi S.S.
        • et al.
        Transport, metabolism, and effect of chronic feeding of cholylsarcosine, a conjugated bile acid resistant to deconjugation and dehydroxylation.
        Gastroenterology. 1990; 98: 163-174
        • Lillienau J.
        • Schteingart C.D.
        • Hofmann A.F.
        Physicochemical and physiological properties of cholylsarcosine. A potential replacement detergent for bile acid deficiency states in the small intestine.
        J Clin Invest. 1992; 89: 420-431
        • Schacht A.C.
        • Sørensen M.
        • Munk O.L.
        • Frisch K.
        Radiosynthesis of N-11C-methyl-taurine-conjugated bile acids and biodistribution studies in pigs by PET/CT.
        J Nucl Med. 2016; 57: 628-633
        • Testa A.
        • Zanda M.
        • Elmore C.S.
        • Sharma P.
        PET tracers to study clinically relevant hepatic transporters.
        Mol Pharm. 2015; 12: 2203-2216
        • Swift B.
        • Yue W.
        • Brouwer K.L.
        Evaluation of (99m)technetium-mebrofenin and (99m)technetium-sestamibi as specific probes for hepatic transport protein function in rat and human hepatocytes.
        Pharm Res. 2010; 27: 1987-1998
        • Testa A.
        • Dall'Angelo S.
        • Mingarelli M.
        • Augello A.
        • Schweiger L.
        • Welch A.
        • et al.
        Design, synthesis, in vitro characterization and preliminary imaging studies on fluorinated bile acid derivatives as PET tracers to study hepatic transporters.
        Bioorg Med Chem. 2017; 25: 963-976
        • Beuers U.
        • Trauner M.
        • Jansen P.
        • Poupon R.
        New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.
        J Hepatol. 2015; 62: S25-S37