illustrates potential distribution sites and excretion pathways relevant for soluble metal complexes, i.e. GBCA. An intravenously administered chelate rapidly equilibrates in the intravascular and interstitial (space between cells) fluid compartments; these are referred to collectively as the extracellular compartment. Depending on its structure, the complex may also be distributed into various intracellular environments (including that of liver and kidney) by passive diffusion or specific uptake processes. Clinically available contrast agents are targeted primarily by their distribution: extracellular fluid agents (ECF agent, also called ECS agents – extracellular space), liver agents, and intravascular or blood pool agents.
Principle distribution sites and excretion pathways for intravenously administered soluble metal complexes
For clinically approved GBCA, there is generally no intracellular distribution apart from the liver in some cases. After intravenous injection, the concentration of GBCA in plasma (Cp
) can be described by a biexponential function, equation 1
From these fitted parameters, secondary pharmacokinetic parameters can be extracted after assuming some sort of model, in this case a two-compartment model and taking into account the dose, usually expressed as mmol Gd per kg body weight. The most common parameters are: 1) the total clearance rate of the GBCA from the blood, Cltot
, which has units of mL per min per kg body weight; 2) the distribution half-life coming from the rate constant a
in eqn 1
, typically denoted α1/2
which has units of time (hr or min); 3) the elimination half-life, β1/2
from rate constant b
in units of time; 4) the area under the serum concentration curve AUC0-t
from administration to time t
. This is usually extrapolated to t
, and has units of concentration multiplied by time, e.g. mM·hr, or μmol·min/L; 5) the volume of distribution at steady state or equilibrium distribution volume, VSS,
expressed as L/kg.
For ECF agents, this number is in the 0.25 L/kg
which reflects the extracellular volume. For a true intravascular agent would about 0.07 L/kg
, the plasma volume. Large volumes of distriubution (> 0.3 L/kg
) would suggest an intracellular distribution.
Extracellular Fluid Agents
The first approved GBCAs were extracellular fluid (ECF) agents. There are several ECF agents approved in the US and Europe and these all behave in a very similar manner, so much so that they are typically referred to simply as “gadolinium” or “gado”. shows the chemical structures of these approved ECF agents.
Figure 3 Chemical structures, chemical names, tradenames, and generic names of approved extracellular fluid (ECF) contrast agents. All 6 are approved for use in the EU, but gadobutrol and gadoterate are not available in the USA. Approval/availability in other (more ...)
Chemically, these compounds exhibit three similar features: they all contain Gd, they all contain an 8-coordinate ligand binding to Gd and they all contain a single water molecule coordination site to Gd. The multidentate ligand is required for safety (2
). The ligand encapsulates the gadolinium resulting in a high thermodynamic stability and kinetic inertness with respect to metal loss. This enables the contrast agent to be excreted intact – an important property since these contrast agents tend to be much less toxic than their substituents. For example, the DTPA ligand and gadolinium chloride both have a LD50
of 0.5 mmol/kg in rats (LD50
= dose that causes death in 50% of the animals), while the Gd-DTPA complex has nearly a factor of 20 higher safety margin, with a LD50
of 8 mmol/kg for the Gd-DTPA complex (3
). The high magnetic moment of the gadolinium ion and the presence of a rapidly exchanging coordinated water molecule are essential to providing contrast. The extracellular agents have very similar properties and these are summarized in . They are all very hydrophilic complexes with similar relaxivities (4
), excellent safety profiles, and can be formulated at high concentrations.
Properties of approved gadolinium-based contrast agents
Upon injection, ECF agents quickly and freely distribute to the extracellular space. The terminal half-life for blood elimination is about 1.5 hrs for all these compounds when administered to subjects with normal renal function (6
). The steady state volume of distribution from various pharmacokinetic studies ranges from 210 to 280 mL/kg consistent with an extracellular distribution. These compounds are eliminated almost exclusively via the kidneys. Because of this, the rate of elimination of ECF agents is reduced in patients with renal disease (11
). Renal function is often assessed using the creatinine clearance rate. The blood elimination half-life of the contrast agent and the clearance rate both show good correlations with creatinine clearance as may be expected for compounds renally excreted. In moderately renally impaired subjects (creatinine rate 30 – 60 mL/min) the contrast agent half-life is increased to 4 – 8 hrs. In severely renally impaired subjects (creatinine < 30 mL/min) the mean half-lifes reported range from 18 to 34 hrs. In these pharmacokinetic studies, recovery of contrast agent from the urine is usually complete by 7 days for subjects with normal and moderately impaired renal function. For normal subjects the compound is >90% recovered after 12 hrs. For subjects with severe renal impairment the percent recovery of Gd goes down with increasing elimination half-life. For instance gadobutrol was 76% recovered after 5 days in patients with creatinine under 10 mL/min (11
Because of their common extracellular distribution, administration of any of these agents yields the same diagnostic information. One exception is in cartilage where the distribution of anionic agents like [GdDTPA]2=
is lower than neutral agents like [GdHP-DO3A] because of repulsion from the negatively charged glycosoaminoglycans (GAGs). This has been exploited in so-called delayed gadolinium enhanced MRI of cartilage (dGEMRIC) where joints with lower GAG content because of e.g. osteoarthritis will appear brighter following GdDTPA administration than joints with normal GAG content (15
). This has been used to quantify GAG content in vivo.
Another consequence, besides NSF, of delayed elimination of ECF agents in subjects with renal insufficiency is that the contrast agent may be able to access different deep compartments. There have been several reports of the cerebrospinal fluid in the subarachnoid space enhancing on images taken 24–48 hrs following Gd administration to renally insufficient subjects despite no underlying pathology in the brain (18
). This is presumably due to slow diffusion of the contrast agent that remains circulating for extended periods. Studies detailing Gd deposition in tissue are discussed below.
Gadobenate and Gadoxetate: ECF + Liver Agents
The ECF agents, like x-ray contrast agents, are cleared almost exclusively renally by glomerular filtration. It was recognized early on that altering the excretion pathway could allow liver imaging. The gadolinium based compounds Gd-BOPTA (gadobenate dimeglumine, Multihance®
) and Gd-EOB-DTPA (gadoxetic acid disodium, sold as Primovist®
in Europe, Eovist®
in USA), , are taken up by hepatocytes (22
) and cleared intact via the hepatobiliary system. Both compounds are based on the stable GdDTPA core and contain a benzyl group that helps target hepatocytes. These gadolinium complexes provide positive contrast (T1 weighted) of the hepatobiliary system. These compounds were originally designed for liver imaging and both show significant hepatobiliary clearance in rats. However in humans gadobenate is only 2–4% hepatically eliminated compared to 50% for gadoxetate; the remainder is renally excreted via glomerular filtration like the ECF agents. The dual elimination pathway renders these agents useful as ECF agents and for liver imaging.
Approved agents with hepatic and ECF distribution
Both compounds show volumes of distribution consistent with extracellular distribution (210 – 280 mL/kg). The aromatic ring confers some weak plasma protein binding to these compounds, although the fraction protein-bound is only about 10%. The weak protein binding results in increased relaxivity compared to ECF agents but does not appear to impact plasma clearance. Gadobenate has a terminal blood half-life on the order of 1.5 – 2 hrs in healthy subjects. For gadoxetic acid the blood half-life is shorter, about 1 hr, and this is probably due to the significant liver uptake of the compound. In patients with hepatic impairment there is little impact on the pharmacokinetics. In patients with renal impairment, the Multihance package insert states that the blood half-life is 6.1 ± 3.0 hrs in moderately impaired subjects (30 < creatinine clearance < 60 mL/min) and 9.5 ± 3.1 hrs in severely renally impaired subjects (10 < creatinine clearance < 30 mL/min). The Eovist/Primovist package insert states in patients with moderate renal impairment a “moderate increase” in terminal half-life was observed compared to healthy volunteers with normal renal function. For patients with end stage renal failure the terminal half-life was prolonged about 12-fold.
Gadofosveset - Blood Pool Agent
Gadofosveset trisodium (MS-325, Vasovist®
), , was approved in the European Union and the USA for peripheral MR angiography. Gadofosveset (23
) is a based on the GdDTPA core and contains a lipophilic biphenylcyclohexyl group that binds reversibly to serum albumin. Albumin is the most abundant protein in plasma, and its concentration is high enough (600–700 μM) to reversibly bind most of the contrast agent after injection. Albumin binding affinity is moderate (Kd = 85 μM) such that the fraction bound to albumin will depend on the concentrations of albumin and the contrast agent (24
). Immediately following injection, when the concentration of the contrast agent is high relative to albumin, there will be a greater free fraction. As the concentration of the contrast agent begins to stabilize (at ~0.5 mM) the fraction bound will become constant.
Structure of the angiography agent gadofosveset (MS-325) showing components which impact its biodistribution and MR signal properties.
The phosphodiester linkage in gadofosveset was shown to limit the hepatic clearance of this compound and as a result gadofosveset is mainly renally excreted (26
). Because albumin binding restricts this compound to the intravascular space, the steady state volume of distribution is 148 ± 16 ml/kg, lower than for the ECF agents. However there is some extravasation and this compound is not 100% confined to the vascular compartment. According to the European Medicines Agency’s scientific discussion document (27
), the terminal plasma half-life of gadofosveset in subjects with normal renal function was 18.5 hrs which is considerably longer than other approved agents and is a result of the albumin binding and lack of hepatic clearance. Gadofosveset was predominantly eliminated in the urine with a small percentage (5%) in the feces. 94% of the urinary excretion occurred within the first 72 hrs of a 14 day collection period. In subjects with moderate and severe renal impairment, the terminal plasma half-life increased 2- and 3-fold, respectively (27