T. Mukai et al., In-vivo evaluation of indium-111-diethylenetriaminepentaacetic acid-labelling for determining the sites and rates of protein catabolism in mice, J PHARM PHA, 51(1), 1999, pp. 15-20
Pharmacokinetic analyses of protein pharmaceuticals are of prime importance
for their clinical application. Because many proteins have pharmacological
activity at low concentrations, radiolabelling of proteins is widely used
to identify the sites and determine the rates of protein catabolism in-vivo
due to the high sensitivity of detection of radioactivity. Recently, a met
allic radionuclide, In-111, has been used to trace the pharmacokinetics of
proteins of interest after conjugation of the proteins with diethylenetriam
inepentaacetic acid (DTPA). In this study, galactosyl-neoglycoalbumin (NGA)
was reacted with the cyclic dianhydride of DTPA and labelled with In-111 t
o estimate the validity of this radiolabelling procedure for pharmacokineti
c analyses, For comparison, we also evaluated direct radioiodination, becau
se directly-radioiodinated proteins are widely used to assess the pharmacok
inetics of proteins of interest.
The hepatic radioactivity profile after intravenous injection of [I-131]NGA
or [In-111]DTPA-NGA into mice was analysed pharmacokinetically, and the fi
rst-order rate constant representing the elimination of the respective radi
ometabolite from hepatic parenchymal cells was determined.
The results indicated that direct radioiodination is inappropriate for purs
uing the pharmacokinetics of the proteins, because of rapid elimination of
the radioactivity from the sites of protein catabolism. These findings also
implied that the [In-111]DTPA label could be used to identify the cataboli
c sites and determine the rates of catabolism of proteins with relatively s
hort biological half-lives, although characterization of radiolabelled spec
ies at the sites of accumulation would be required for accurate determinati
on of the catabolic sites of proteins.