Digital simulation of dissociation of paramagnetic contrast agents based onstructural and biophysic parameters of linear and cyclic complexes of gd3+: prognosis of toxic complications risk.

Ussov W.Yu, Bakhmetyeva M.I., Savello N.V., Shimanovsky N.L.

Purpose. To estimate the release of Gd (III) from the contrast agents using special phenomenologic pharmacokinetic multicompartment model. Materials and methods. Basing on phenomenologic multicompartment model of kinetic of cyclic and linear paramagnetic contrast agents with Gd we evaluated the kinetic of dissociation in plasma due to transmetallation with microelements (Zn, Co и Mn). The model comprised the compartments of blood plasma (as central one), of muscle and connective tissue, of liver, of kidney, with calculation of constants of direct (plasma-to-tissue) and back (tissue-to-plasma) transfer. In order to calculate the real constants of transport the data of dynamic MRI studies were employed, in particular T1-w SE frontal plane dynamic scanning of contrast distribution over head, chest and upper abdomen and retroperitoneal region (TR=15 ms, TE=500 ms, matrix 256х392, scan as short as 15-30 с). Tissue dissociation of paramagnetics has been simulated on the basis of competitive transmetallation of Gd with microelements, according to transmetallation scheme proposed by F.Kalman and G.Tyrsco. As integral indices of stability of contrast agents the thermodynamic stability constant Ктерм , и «кажущейся»(при pH=7,4) стабильности were employed. There were simulated the kinetic and dissociation processes of gadodiamide (Кtherm = 16,9; КpH=7,4 = 14,9 ); gadopentetate bimegluminate(Кtherm = 22,1; КpH=7,4 = 18,3), gadobutirol (Кtherm = 21,8; КpH=7,4 = 17,2), gadoversetamide (Кtherm = 17; КpH=7,4 = 15 ). It was assumed in all cases the contrast was instantly injected and distributed in the central compartment (blood plasma). The simulation model was implemented using MatLab and SciLab. Results. When simulating the transmetallation of paramagnetics using this phenom-enologic model there was no significat release of Gd for over 20% of the injected dose in case of linear complexes of Gd down to glomerular filtration rate as low as 32-33 ml/min/1,73sqm, and in case of cyclic stable complexes of Gd down to GFR = 25 ml/min/1,73sqm. The tissue retention of contrast paramagnetic was determined essentially by ratio of direct and back transfer constants, and was obvious only in brain glial tumor, in which this ratio was maximal both for linear paramagnetic contrasts (in particular for gadodiamide kplasma-tumor = 5,87 ± 0,31 ml/min/100cm3; ktumor-plasma = 0,91±0,23 ml/min/100cm3), and for cyclic ones (for gadobutirol kplasma-tumor = 5,42 ± 0,37 ml/min/100cm3; kопухоль-плазма = 0,71 ± 0,17 ml/min/100cm3 ). Conclusion. Pharmacokinetic and pharmacodynamic simulation of dissociation of paramagnetic contrast agents with current indexes of kinetic stability shows abrupt rise in release of free Gd in plasma over 20% with concomitant risk of toxicity in cases of GFR below 33 ml/min/1,73 sqm when employing linear contrast agents, and with cyclic contrast when GFR below 25 ml/min/1,73 sqm.
1 - Institute of Cardiology, Tomsk National Medical Research Center of the Russian Academy of Sciences. Tomsk, Russia 2 - Department of Mechanics and Mathematics, M.V. Lomonosov Moscow State University. 3 - R-Pharm. Moscow, Russia. 4 N.I. Pirogov Russian National research medical University, P.V.Sergeev department of molecular pharmacology and radiobiology. Moscow, Russia.


 

 

 

 

 

 

Keywords:magnetic resonance imaging, paramagnetic contrast enhancement, Gadolinium, phar-macokinetic simulation, toxicity risk.

 

Corresponding author:Ussov W.Yu., e-mail: Этот e-mail адрес защищен от спам-ботов, для его просмотра у Вас должен быть включен Javascript

 

For citation: Ussov W.Yu, Bakhmetyeva M.I., Savello N.V., Shimanovsky N.L. Digital simulation of dissociation of paramagnetic contrast agents based onstructural and biophysic parameters of linear and cyclic complexes of gd3+: prognosis of toxic complications risk. REJR 2017; 7(4):117-129. DOI:10.21569/2222-7415-2017-7-4-117-129.

Received: 06.09.2017 Accepted: 20.11.2017