TY - JOUR
T1 - Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans
AU - Kirk, Frederik
AU - Munk, Ditte Emilie
AU - Swenson, Eugene Scott
AU - Quicquaro, Adam Michael
AU - Holm Vendelbo, Mikkel
AU - Schilsky, Michael L.
AU - Ott, Peter
AU - Sandahl, Thomas Damgaard
PY - 2024/5
Y1 - 2024/5
N2 - Background and Aims: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. Approach and Results: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 (
64Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the
64Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic
64Cu uptake reflect the effect of drugs on intestinal absorption.
64Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic
64Cu activity 1 hour after
64Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p<0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p<0.02, indicating strong inhibition of intestinal
64Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p<0.04. Conclusions: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
AB - Background and Aims: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. Approach and Results: Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 (
64Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the
64Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic
64Cu uptake reflect the effect of drugs on intestinal absorption.
64Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic
64Cu activity 1 hour after
64Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p<0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p<0.02, indicating strong inhibition of intestinal
64Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p<0.04. Conclusions: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
KW - 64 copper
KW - copper absorption
KW - PET
KW - copper chelation
KW - randomized
KW - rare disease
KW - copper
KW - trientine
KW - penicillamine
KW - D-penicillamine
KW - cuprior
KW - cufence
KW - metalcaptase
KW - Copper Radioisotopes/therapeutic use
KW - Humans
KW - Penicillamine/pharmacology
KW - Positron-Emission Tomography
KW - Hepatolenticular Degeneration/drug therapy
KW - Positron Emission Tomography Computed Tomography
KW - Copper
KW - Trientine/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85190826164&partnerID=8YFLogxK
U2 - 10.1097/HEP.0000000000000708
DO - 10.1097/HEP.0000000000000708
M3 - Journal article
C2 - 38088886
SN - 0270-9139
VL - 79
SP - 1065
EP - 1074
JO - Hepatology
JF - Hepatology
IS - 5
ER -