Delving into the Latest Updates on 11C-cholylsarcosine(University of Aarhus) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug, Diagnostic radiopharmaceuticals

Synonyms

11C-CSAR

Target-

Action-

Mechanism-

Therapeutic Areas

Digestive System DisordersOther Diseases

Active Indication-

Inactive Indication

Cholangitis, SclerosingPrimary Biliary Cholangitis

Originator Organization

University of Aarhus

Active Organization-

Inactive Organization

University of Aarhus

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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It is not known how hepatic bile acids transport kinetics changes postprandially in the intact liver. We used positron emission tomography (PET)/computed tomography (CT) with the tracer [N-methyl-¹¹C]cholylsarcosine (¹¹C-CSar), a synthetic sarcosine conjugate of cholic acid, to quantify fasting and postprandial hepatic bile acid transport kinetics in healthy human participants.

METHODS:

Six healthy human participants underwent dynamic liver ¹¹C-CSar PET/CT (60 min) during fasting and from 15 min after ingestion of a standard liquid meal. Hepatobiliary secretion kinetics of ¹¹C-CSar was calculated from PET data, blood samples (arterial and hepatic venous) and hepatic blood flow measured using indocyanine green infusion.

RESULTS:

In the postprandial state, hepatic blood perfusion increased on average by 30% (p <0.01), and the flow-independent hepatic intrinsic clearance of ¹¹C-CSar from blood into bile increased by 17% from 1.82 (range, 1.59-2.05) to 2.13 (range, 1.75-2.50) ml blood/min/ml liver tissue (p = 0.042). The increased intrinsic clearance of ¹¹C-CSar was not caused by changes in the basolateral clearance efficacy of ¹¹C-CSar but rather by an upregulated apical transport, as shown by an increase in the rate constant for apical secretion of ¹¹C-CSar from hepatocyte to bile from 0.40 (0.25-0.54) min^-1 to 0.67 (0.36-0.98) min^-1 (p = 0.03). This resulted in a 33% increase in the intrahepatic bile flow (p = 0.03).

CONCLUSIONS:

The rate constant for the transport of bile acids from hepatocytes into biliary canaliculi and the bile flow increased significantly in the postprandial state. This reduced the mean ¹¹C-CSar residence time in the hepatocytes.

LAY SUMMARY:

Bile acids are important for digestion of dietary lipids including vitamins. We examined how the secretion of bile acids by the liver into the intestines changes after a standard liquid meal. The transport of bile acids from liver cells into bile and bile flow was increased after the meal.

01 Aug 2017·Journal of hepatologyQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Munk, Ole Lajord ; Frisch, Kim ; Sørensen, Michael ; Keiding, Susanne ; Ott, Peter ; Ørntoft, Nikolaj Worm

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, 0.005-0.07min^-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min^-1, 2.3times 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).

100 Deals associated with 11C-cholylsarcosine(University of Aarhus)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cholangitis, Sclerosing	Phase 1	Denmark	University of Aarhus	01 Jun 2013
Primary Biliary Cholangitis	Phase 1	Denmark	University of Aarhus	01 Jun 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EASL2019	Not Applicable	-	6	11C-CSar (Fasting)	jngijmrbth(rrkzkgnoff) = yccdsskuhu qdakvhyidj (nxcbbqyvjz, 2.21 - 5.22) View more	-	11 Apr 2019
				11C-CSar (Postprandial)	jngijmrbth(rrkzkgnoff) = rhpjoevjoz qdakvhyidj (nxcbbqyvjz, 2.21 - 5.22) View more
NCT03253276 \| NCT01879735 (Pubmed \| J Hepatol)	Not Applicable	-	-	<sup>11</sup>C-CSar (Healthy participants)	kiywryvyxw(mjgxksbqnx) = vxymntcxtk oeipmbmmzm (drwnfzjjzk, 1.20 - 1.76)	-	01 Aug 2017
				<sup>11</sup>C-CSar (Patients with varying degrees of cholestasis)	kiywryvyxw(mjgxksbqnx) = uzehvfzjqb oeipmbmmzm (drwnfzjjzk, 0.13 - 0.91)
NCT01879735 (CTgov)	Phase 1	Cholangitis, Sclerosing \| Primary Biliary Cholangitis	22	11C-CSar+ICG (Infusion Method)	lfqxspgtjo = tsjpjklghn xlwbqpadrg (kjolnwqtds, osaoczecqt - rcefuevtkm)	-	23 Feb 2015
				11C-CSar+ICG (ICG's Effect on 11C-CSar Transport)	mqueffnwhm(dxyzublkbc) = jtttpbujgc catdnjjlhe (odrnwbshmj, yppsyiylni - nqgduscebj) View more