MAGMA M a g n e t i c R ~ . o r m n c e M a t e r i ~ d s in Physic.% Biolc~g~" a n d M c ~ l i c i n e
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Magnetic Resonance Materials in Physics, Biology and Medicine 12 (2001) 82-87
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Comparison of plasma and peritoneal concentrations of various categories of MRI blood pool agents in a murine experimental pharmacokinetic model F. Bourasset, A. Dencausse, P. Bourrinet, M. Ducret, C. Corot * Guerbet, Bio~gical Research Department, B.P. 50400, 95943 Roissy Chart~'s De GaulTe, Cede.v, France
Received 7 December 2000; accepted 14 December 2000
Abstract
The aim of this study was to validate an experimental model designed to distinguish four categories of contrast agents, non specific agents (NDA, Gd-DOTA) characterized by rapid and total extravasation: low diffusion agents (LDA, P760) characterized by delayed extravasation; and rapid (P792) and slow clearance (P717) blood pool agents (BPA) characterized by limited extravasation. Plasma and peritoneal gadolinium concentrations were simultaneously measured after intravenous injection of various contrast agents in mice. Products of each category were compared in this model. The plasma pharmacokinetic profiles were similar for Gd-DOTA and P760 (t 1/2 = 13.3 and 13.8 min, respectively), whereas the half-lives were 22 and 1212 min for P792 and P717, respectively. The plasma clearance was inversely related to the size of the contrast agent. The intraperitoneal diffusion patterns of the various products were related to the molecular volume: Cm~,~per dose decreased progressively (78.7, 51.2, 44.2, 33.5 I/1) and t ..... increased (7, 15, 40, and 120 min) for Gd-DOTA, P760, P792 and P717, respectively. Nevertheless, the same quantities of Gd-DOTA and P760 (AUC ratio of 78,4 and 76.8, respectively) diffused into the peritoneum, whereas only 44.5% of P792 and 21.5% of P717 extravasated. The data obtained in this peritoneal permeability model with the various categories of contrast agents provide an estimation of the quantities of contrast agents diffusing into a permeable interstitium and may be used to predict the corresponding signal intensity, which can be measured locally. 9 2001 Elsevier Science B.V. All rights reserved. Kevwords: Peritoneum; Pharmacokinetic: Blood pool contrast agent; MRI; Mice; Gadolinium
1. Introduction
Following intravenous injection, non specific agents (NSA), such as G d - D O T A , diffuse rapidly into the interstitium, except in the normal brain. In the case of angiography or perfusion imaging (except in the brain), extravasation of these compounds increases the background signal of the surrounding tissues leading to a decrease in the contrast (CNR) [1]. Clinical tumor characterization by dynamic contrast-enhanced M R I is based on kinetic measurement of the permeability of NSA through tumor endothelium, which is more permeable than normal endothelium [2]. However, these * Corresponding author. Tel.: + 33-1-45915068; fax: + 33-145915123. E-mail address:
[email protected] (C. Corot).
compounds are too small to accurately differentiate tumors from normal tissue [3]. Blood pool agents (BPA) are more adapted to determine tumor permeability due to their higher molecular volume [4,5], allowing a better distinction between normal and tumor endothelium. Various categories of BPA have been described (Fig. 1); this classification is based on their global ability to cross the endothelium and to filter through the renal glomeruli [6]. Rapid clearance BPA (RCBPA, Fig. l c) are mainly confined to the vascular space, but are freely excreted by the kidneys [7], whereas the renal excretion of slow clearance BPA (SCBPA, Fig. l d) is very restricted [8]. Low diffusion agents (LDA, Fig. l b) have an intermediate position between NSA and BPA [9], and their
1352-866101/$- see front matter ~g~2001 Elsevier Science B.V. All rights reserved. PII: S1352-8661(01)00104-1
83
F. Bourasset et a l . / Magnetic Resonance Materials in Physics, Biology and Medicine 12 (2001) 82-87
IV
Non Specific Agent
Low Diffusion Agent
lkl,O UrLne
rv
1
Urine
lkl,O . Free endothelial permeability . Free renal excretion
Urine
RCBPA
. Slow endothelial permeability . Free renal excretion
SCBPA
rv
. No endothelial permeability . Free renal excretion
Urine
. No endothelial permeability . Restricted renal excretion
Fig. 1. Pharmacokinetic classifications of the various categories of contrast agents. (a) NSA, non specific agent; (b) LDA, low diffusion agent; (c) RCBPA, rapid clearance blood pool agent; (d) SCBPA, slow clearance blood pool agent.
interstitial diffiasion occurs a t a lower rate than with NSA (Fig. la). The aim of this study was to validate an experimental model designed to distinguish the four categories of contrast agents. Plasma and peritoneal concentrations were simultaneously determined after intravenous injection of various contrast agents in mice. Products of each category were compared in this model.
2.3. Experimental protocol Each product was injected by intravenous bolus into the caudal vein. Mice were sacrificed at various times (Table 2) by decapitation in order to limit blood extravasation into the peritoneum, and blood samples were collected from the aorta in a heparinized test tube Table 1 Main characteristics of the various compounds Gd-DOTA
2. Material and methods
2. I. Animals All animal experiments were performed in compliance with the EEC directive (86/609/EEC) on animal welfare. Non-anaesthetised male ICR CD1 mice (Harlan, France), weighing 18-20 g, were used.
Pharmacokinetic NSA category MW (kDa) 0.56 Mean diameter 1 (nm) Concentration 500 solution (mM) Dose 3 (mmol/kg) Injected (gmol) 69.5
P760
P792
P717
LDA
RCBPA
SCBPA
5.29 2.8 70
0.75 16.7
6.47 5.05 34
0.4 8.45
52 Not determined 98
0.75 16.5
2.2. Prochtcts Gd-DOTA (NSA, Dotarem ~':'~, Guerbet), P760 [9] (LDA, Guerbet Research), P792 [7] (RCBPA, Guerbet Research) and P717 [8] (SCBPA, Guerbet Research) were tested. P760 and P792 are monodispersed monogadolinium macrocyclic chelate derivatives, whereas PT17 is a polydispersed polygadolinium chelate dextran derivative. The main physicochemical characteristics of these four products are presented in Table 1.
Table 2 Sample times Product
Sample times
Gd-DOTA P760
35 s, 35 s, 120' 3', 7', 1', 7',
P792 P717
50 s, 1', 3', 5', 7', 15', 30', 60', 120', 150' 50 s, 1', 3', 5', 7', 15', 30', 60', 70', 80', 100', 20', 40', 60', 90', 120' 20', 60', 120', 240', 360', 24 h, 48 h
/7. Bourasset et al./Magnetic Resonance Materkds #l Physics, Bioh)gy and Medicine 12 (2001) 82-87
84
200(;0
--e--plasma
Gd-DOTA
prnolJI 15(~3
--1--ip
8000 :[_ prnol./f
---e--- plasrra
P760
- - u - - ip 6000 I
10000
4000
5(XX~
2000 rnin
0
0 0
(a)
10
20
30
6000
P792 5000
40
50
~
60
plasrr~
--ta--ip
4000
(b)
30
o
60
15000 pmoi.i1 12000
90
120
--e--- plasma
P717
--ia-- ip
9000 6000
1000
min
~
3~
~
hour I;
0
0
0
(c)
-
50
100
150
(d) o
6
12
18
24
30
36
42
48
Fig. 2. Plasma and intrapcritoneal concentrations o[" various categories of contrast agents. (a) Gd-DOTA, NSA: (b) P760, LDA: (c) P792, RCBPA: (d) P717, SCBPA.
80
700
~P717 600
....r
70
~P760
~P760 1, .....Gd-DOTA
500
60
.......--- Gd-DOTA F792
50
------ P792
"= 400
P717
40
3OO
,r
30
200
20
100
10 0 0
20
40
60
80
100 ..... 120
(a)
(b)
0
20
40
60
80
100 rnin 120
Fig. 3. Pharmacokinetic comparison of the various categories of contrast agents. (a) Plasma concentrations: (b) intraperitoneal concentrations.
(Choay, set 1926). Blood samples were centrifuged at 3000 rpm for 10 min. Immediately after sacrifice, 2 ml of Ringer lactate were injected into the peritoneal cavity (Lavoisier, set 18240) and, after gentle abdominal massage, 1 ml of peritoneal fluid was collected. Six mice per time-point were sacrificed for the first 15 rain (greater variability at early time-points) and three mice per time-point were sacrificed at the subsequent time-points. As diffusion of the various contrast agents from blood into the peritoneal cavity varies according to their molecular volume, the sample times were adapted for each product (Table 2). Gd-DOTA and P760 were
sampled at earlier times than P792, while the time window for P717 was 48 h. A high dose of Gd-DOTA was used (3 mmol/kg) in order to have detectable blood concentrations during all the sampling period. Table 3 Plasma pharmacokinetic parameters
t 1/2 t3 (min) Clt (ml/min per kg) Vd 13 (ml/kg) C5/Co%
Gd-DOTA
P760
P792
P717
13.3 18 346 14.3
13.8 9 216 22.1
22 4.8 128 80.4
1212 0.17 206 82.7
F. Bourasset et a l . / Magnetic Resommce Materials in Physics, Biology and Medichw I2 (200I) 82-87 Table 4 Intraperitoneal pharmacokinetic parameters
Cm~,x per dose (1/1) Tm,,x (min) Lag time A U C I P / A U C I V (%)
85
3. Results
Gd-DOTA
P760
P792
P717
78.7 7
