In the rat hippocampal region, a single intracerebral injection of gadoteridol (1 mM) increases rAAV1 distribution [1].

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Co-infusion of Gadoteridol with recombinant adeno-associated virus serotype 1 encoding green fluorescent protein (rAAV1-GFP) into the rat dorsal hippocampus significantly increased the distribution of the transgene compared to co-infusion with Lactated Ringer's solution. This was quantified by a 1.5-fold increase in mean optical density (OD), a 2.2-fold increase in mean area above threshold (AAT), and a 1.8-fold increase in the volume of distribution (Vd) within the injected hippocampal hemisphere. Enhanced GFP distribution was also observed in the contralateral hemisphere and in cortical areas adjacent to the injection track, suggesting Gadoteridol facilitated both anterograde and retrograde transport of the viral vector or its product. In contrast, co-infusion of Gadoteridol with rAAV5-GFP did not significantly alter the distribution of GFP in the injected or contralateral hippocampus. [1]

Animal/Disease Models: SD (SD (Sprague-Dawley)) rats (3 -5 months) [1]
Doses: 1 mM/rat
Route of Administration: Intracerebral injection once, co-infusion with rAAV1 or AAV5
Experimental Results: Increased transduction efficiency of AAV1, But AAV5 is not added.

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Adult Sprague-Dawley rats (3-5 months old) were used. For intracerebral injections, animals were placed in a stereotaxic frame. Gadoteridol was diluted in Lactated Ringer's solution to a working concentration. For experimental groups, a mixture of 1 µL Gadoteridol and 1 µL viral vector (rAAV1-GFP or rAAV5-GFP) was prepared, resulting in a final 1 mM concentration of Gd. Control animals received 1 µL viral vector mixed with 1 µL Lactated Ringer's solution only. A total volume of 2 µL was infused unilaterally or bilaterally into the dorsal hippocampus at a rate of 0.5 µL/min using an infusion pump. After infusion, the needle was left in place for 1 minute, then raised 3 mm and left for an additional 4 minutes before withdrawal from the brain. [1]
Behavioral assessments were conducted to evaluate hippocampal function. The Object Location Memory (OLM) task was performed three weeks post-injection. Rats were trained with two identical objects for six minutes. Testing occurred 24 hours later, with one object moved to a novel location. Exploration times were recorded and a novelty score was calculated. [1]
The Morris Water Maze (MWM) task was performed two days after the OLM task. Animals were first habituated with a visible platform. Subsequently, they were trained for five days to locate a hidden submerged platform using spatial cues. The distance traveled to find the platform was recorded daily. A probe trial (platform removed) was conducted after the last training trial to measure the time and distance spent in the target quadrant. [1]

Absorption, Distribution and Excretion
Based on population pharmacokinetic models of pediatric subjects who received a single intravenous injection of 0.1 mmol/kg gadolinium, the mean Cmax was 0.66 ± 0.21 mmol/L for pediatric subjects aged 2 to 6 years, 0.58 ± 0.06 mmol/L for pediatric subjects aged 6 to 12 years, and 0.68 ± 0.12 mmol/L for adolescents aged 12 years and older. The mean AUC0-∞ was 0.74 ± 0.20 mmol/Lh for children aged 2 to 6 years, 0.74 ± 0.09 mmol/Lh for children aged 6 to 12 years, and 0.98 ± 0.09 mmol/Lh for adolescents aged 12 years and older. Pharmacokinetic simulations showed that the ProHance half-life, AUC, and Cmax values were similar in children under 2 years of age compared to adults. Within 24 hours of injection, 94.4 ± 4.8% (mean ± standard deviation) of the dose was excreted in the urine. After 10 hours, more than 80% of the dose was recovered in the urine of pediatric subjects. In patients with moderate and severe renal impairment, approximately 97% and 76% of the administered dose, respectively, were excreted in the urine within 7 and 14 days. The plasma volume of distribution (mean ± standard deviation) in adults with normal renal function was 0.205 ± 0.025 L/kg. Following injection of gadolinium contrast agents, gadolinium can remain in the brain, bone, skin, and other organs for months or years. The renal and plasma clearances of gadolinium-specific alcohol (1.41 ± 0.33 mL/min/kg and 1.50 ± 0.35 mL/min/kg, respectively) were essentially the same, indicating that its elimination kinetics via the kidneys were unchanged and that the drug is primarily cleared by the kidneys. The mean serum gadolinium clearance rate was 116.14 ± 26.77 mL/min in patients with normal renal function, 37.2 ± 16.4 mL/min in patients with mild to moderate renal impairment, and 16.0 ± 3.0 mL/min in patients with severe renal impairment. This study investigated the physicochemical properties of gadolinium (a macrocyclic nonionic gadolinium complex), as well as its pharmacokinetics and biodistribution in rats and dogs. In rat studies, a single intravenous injection of 0.1 or 0.35 mmol/kg of (153)Gd-labeled gadolinium, or daily injection of 0.1 mmol/kg for 7 consecutive days, was used to detect residual gadolinium levels in various organs. In dogs, non-radioactive biodistribution and excretion studies were conducted after injection of 0.1 mmol/kg. Following injection, the drug was rapidly cleared from the rat bloodstream and excreted; within 4 hours of injection, over 90% of the dose appeared in the urine. At 7 and 14 days post-injection, extremely low levels of gadolinium were observed only in the liver and bones; these levels were 2 to 8 times lower than those reported after gadopentetate meglumine injection. ...The difference in long-term gadolinium retention observed between gadolinium-1,000 and gadopentetate meglumine is consistent with the reported higher in vivo metal transfer resistance of gadolinium macrocyclic compounds compared to linear gadolinium chelate molecules. To evaluate the safety and pharmacokinetics of gadolinium-1,000 injection (0.5 M), 18 healthy male volunteers were randomly assigned to six dosing groups: 0.05, 0.1, 0.15, 0.2, 0.25, and 0.3 mmol/kg gadolinium-1,000 (0.5 M), in an escalating dose study. Physical examination, vital signs, electrocardiograms, clinical laboratory test results, and serum and urine samples were collected from subjects at specific time points before and after gadolinium-1,000 injection. ...No significant changes in vital signs, physical examination, clinical laboratory values, or electrocardiograms related to contrast agent administration were observed. One volunteer experienced an adverse event (transient urticaria), believed to be related to contrast agent administration. Pharmacokinetic data showed that the elimination half-life and distribution half-life were not dose-dependent. The mean distribution half-life was 0.20 ± 0.04 hours, and the mean elimination half-life was 1.57 ± 0.08 hours. Over 94% of the drug was excreted in the urine within 24 hours. Within 24 hours of injection, 94.4 ± 4.8% (mean ± standard deviation) of the dose was excreted in the urine. Gadolinium cannot cross the intact blood-brain barrier and therefore does not accumulate in normal brain tissue or lesions with a normal blood-brain barrier (e.g., cysts, mature postoperative scars, etc.). However, disruption of the blood-brain barrier or vascular abnormalities can lead to the accumulation of gadolinium in lesions such as tumors, abscesses, and subacute infarctions. The pharmacokinetics of ProHance in various lesions are unknown. For more complete data on the absorption, distribution, and excretion of gadolinium (7 types), please visit the HSDB record page. Metabolites/Metabolites: Whether gadolinium undergoes biotransformation or degradation in vivo is unknown. The elimination half-life (mean ± standard deviation) is approximately 1.57 ± 0.08 hours. Based on a population pharmacokinetic model of pediatric subjects receiving a single intravenous injection of 0.1 mmol/kg gadolinium, the mean distribution half-life (t_1/2,α) was 0.14 ± 0.04 hours for pediatric subjects aged 2–6 years, 0.18 ± 0.07 hours for pediatric subjects aged 6–12 years, and 0.20 ± 0.07 hours for adolescents aged 12 years and older. The mean elimination half-life (t_1/2,β) was 1.32 ± 0.006 hours in pediatric subjects aged 2–6 years, 1.32 ± 0.07 hours in pediatric subjects aged 6–12 years, and 1.61 ± 0.19 hours in adolescent subjects aged 12 years and older. Pharmacokinetic simulations showed that the half-life of gadolinium in children under 2 years of age was similar to that in adults. The serum half-life of gadolinium was prolonged in patients with impaired renal function. Following intravenous administration of 0.1 mmol/kg gadolinium, the elimination half-life was 10.65 ± 0.06 hours in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min) and 9.10 ± 0.26 hours in patients with severe renal impairment who were not on dialysis (creatinine clearance 10–30 mL/min).
The pharmacokinetics of intravenously administered gadolinium in healthy subjects conformed to a two-compartment open model, with a mean distribution half-life and elimination half-life (expressed as mean ± standard deviation) of approximately 0.20 ± 0.04 hours and 1.57 ± 0.08 hours, respectively.
…18 healthy male volunteers…were randomly assigned to six dosing groups: 0.05, 0.1, 0.15, 0.2, 0.25, and 1.57 ± 0.08. In the dose escalation study, subjects were given 0.3 mmol/kg of gadolinium (0.5 M). …Pharmacokinetic data showed that the elimination half-life and distribution half-life were independent of the dose used. The mean distribution half-life was 0.20 ± 0.04 hours, and the mean elimination half-life was 1.57 ± 0.08 hours…

Toxicity Summary
Identification and Use: Gadolinium is used as an injectable contrast agent for magnetic resonance imaging (MRI). Human Exposure and Toxicity: Gadolinium-based contrast agents (GBCAs) increase the risk of developing renal systemic fibrosis (NSF) in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained via non-contrast MRI or other means. NSF can cause fatal or disabling systemic fibrosis affecting the skin, muscles, and internal organs. The risk of NSF is highest in patients with chronic severe kidney disease or acute kidney injury. Patients should be screened for acute kidney injury and other conditions that may impair kidney function. For patients at risk of chronic kidney decline (age 60 or older, hypertension, or diabetes), glomerular filtration rate (GFR) should be estimated by laboratory tests. For patients at high risk of renal systemic fibrosis (NSF), do not exceed the recommended ProHance dose and allow sufficient time for the drug to be cleared from the body before re-administering. The possibility of adverse reactions should always be considered, including severe, life-threatening, or fatal anaphylactic or cardiovascular reactions, or other specific reactions, especially in patients with a known history of clinical hypersensitivity or asthma or other allergic respiratory diseases. One case of vasovagal reaction and anaphylactic-like reaction during intravenous gadolinium administration has been reported in the literature. In vitro studies have shown that gadolinium, even at high concentrations, did not exhibit hemolytic potential when incubated with whole blood, suggesting that gadolinium is unlikely to cause hemolysis in vivo. Animal studies: In mice, gadopentetate meglumine (Magnevist), gadolinium (ProHance), gadodiamine (Omniscan), and gadovitamide (Optimark) were evaluated at standard concentrations and compared with a control group (normal saline) and the conventional ionizing contrast agent iohexol meglumine (Renografin 60). Of the four magnetic resonance imaging (MRI) contrast agents, gadopentetate meglumine caused the greatest tissue damage, while the two agents with the lowest osmotic pressure—Gadoteridol and gadodiamine—caused the least tissue damage after subcutaneous injection in the hind limbs. In pregnant rats, administration of ProHance at a dose of 10 mmol/kg/day for 12 consecutive days (equivalent to 33 times the maximum recommended human dose of 0.3 mmol/kg, or 6 times the human dose on a mmol/m² basis) resulted in a doubling of the incidence of post-implantation embryo loss. In rats, administration of ProHance at doses of 6.0 or 10.0 mmol/kg daily for 12 consecutive days increased spontaneous kinetic activity in their offspring. In pregnant rabbits, administration of ProHance at a dose of 6 mmol/kg daily for 13 consecutive days (equivalent to 20 times the maximum recommended human dose, or 7 times the human dose on a mmol/m² basis) showed an increased incidence of spontaneous abortion and preterm birth. ProHance showed no genotoxic activity in bacterial reverse mutation assays in Salmonella and Escherichia coli, positive mutation assays in mouse lymphoma, in vitro cytogenetic assays measuring the frequency of chromosomal aberrations in Chinese hamster ovarian cells, and in vivo mouse micronucleus assays at intravenous doses up to 5.0 mmol/kg.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Gadotol is one of the most stable gadolinium contrast agents and is theoretically one of the safest drugs for use during lactation. Guidelines developed by multiple professional organizations indicate that breastfeeding women do not need to interrupt breastfeeding after receiving gadolinium-containing contrast agents. However, since there is currently no published experience on the use of gadotol during lactation, other drugs may be preferred, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein Binding
It is currently unclear whether gadoteridol undergoes protein binding in vivo.Non-human Toxicity
Mouse Intravenous LD50: 11-14 mmol/kg/gadoteridol injection/
Rat Intravenous LD50: >10 mmol/kg/gadoteridol injection/

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Co-infusion of gadoteridol and rAAV1-GFP into the rat hippocampus did not impair spatial memory formation in rats (assessed by Morris water vagal nerve stimulation). Maze and object location memory tasks. Animals treated with gadoteridol/rAAV1 performed statistically similarly to the control group treated with Ringer's solution/rAAV1 in both tasks. [1]
Histological analysis showed that, apart from slight changes around the needle tract, no significant cell damage or extensive astrocyte proliferation (assessed by GFAP immunostaining) was observed in the hippocampus after co-infusion of Gadoteridol with rAAV1 or rAAV5 (as assessed by GFAP immunostaining). However, enhanced Iba1 immunoreactivity was observed in the hippocampus co-injected with Gadoteridol and rAAV5, indicating microglia activation, although this enhancement was not statistically significant in terms of distribution parameters compared to the Ringer's solution/rAAV5 control group. [1]
Literature indicates that infusion of Gadoteridol may have adverse effects in patients with pre-existing kidney disease. However, it has also been used in animal models and human studies without any signs of toxicity. [1]

[1]. The MRI contrast agent gadoteridol enhances distribution of rAAV1 in the rat hippocampus. Gene Ther. 2013 Dec;20(12):1172-7.

Gadoteridol is a macrocyclic nonionic gadolinium that enhances contrast in the brain, spinal cord, and surrounding tissues, thereby improving the visualization of lesions with abnormal angiogenesis or those believed to have disrupted the normal blood-brain barrier (compared to unenhanced MRI). It is one of three macrocyclic gadolinium-based contrast agents mandated by the European Medicines Agency (EMA) to replace linear gadolinium-based contrast agents due to concerns about gadolinium residues in the brain. Gadoteridol was initially approved by the U.S. Food and Drug Administration (FDA) in 1992 and approved for use in children under 2 years of age in 2020. Gadoteridol is a paramagnetic contrast agent. Its mechanism of action is as a magnetic resonance imaging (MRI) contrast agent. Indications: Gadoteridol is indicated for use on magnetic resonance imaging (MRI) to visualize lesions of the brain, spinal cord, and related tissues in adults and children, including full-term newborns, that show disruption of the blood-brain barrier and/or vascular abnormalities. It is also indicated for visualization of lesions in the head and neck of adults.
FDA Label

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Mechanism of Action
Gadotyl alcohol is a paramagnetic contrast agent, and therefore, when placed in a magnetic field, it generates a magnetic moment. The relatively large magnetic moment generated by the paramagnetic contrast agent results in a relatively large local magnetic field, thereby enhancing the relaxation rate of water protons near the paramagnetic contrast agent. In MRI, the imaging portions of normal and diseased brain tissue depend on variations in radiofrequency signal intensity, which are caused by: 1) differences in proton density; 2) differences in spin-lattice or longitudinal relaxation time (T1); and 3) differences in spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadotyl alcohol reduces the T1 relaxation time of the target tissue. At the recommended dose, the effect is most pronounced in T1-weighted sequences.

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Therapeutic Use
Contrast Agent
ProHance (gadolinium) injection is indicated for MRI examinations in adults and children 2 years of age and older to visualize lesions with vascular abnormalities in the brain (intracranial lesions), spine, and related tissues. /Included on US product label/
ProHance is indicated for MRI examinations in adults to visualize lesions in the head and neck. /Included on US product label/

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Drug Warnings
/Black Box Warning/ Warning: Renal Systemic Fibrosis. Gadolinium-based contrast agents (GBCAs) increase the risk of developing renal systemic fibrosis (NSF) in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained by non-contrast MRI or other means. NSF can cause fatal or disabling systemic fibrosis affecting the skin, muscles, and internal organs. The risk of NSF is highest in patients with chronic severe kidney disease (glomerular filtration rate (GFR) <30 mL/min/1.73 m²) or acute kidney injury. Patients should be screened for acute kidney injury and other conditions that may impair kidney function. For patients at risk of chronic kidney function decline (e.g., age > 60 years, hypertension, or diabetes), GFR should be estimated by laboratory tests. For patients at high risk of renal systemic fibrosis (NSF), do not exceed the recommended ProHance dose and allow sufficient time for drug clearance before re-administration. Gadolinium contrast agents (GBCAs) increase the risk of NSF in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained by non-contrast MRI or other examinations. The risk of GBCA-related NSF appears to be highest in patients with chronic severe kidney disease (glomerular filtration rate (GFR) <30 mL/min/1.73 m²) and patients with acute kidney injury. The risk appears to be low in patients with chronic moderate kidney disease (GFR 30–59 mL/min/1.73 m²), while the risk is minimal or even nonexistent in patients with chronic mild kidney disease (GFR 60–89 mL/min/1.73 m²). Renal systemic fibrosis (NSF) can lead to fatal or disabling fibrosis, affecting the skin, muscles, and internal organs. …Screen patients for acute kidney injury and other conditions that may impair kidney function. Acute kidney injury is characterized by a rapid (within hours to days) and usually reversible decline in kidney function, commonly seen in cases of nephrotoxicity caused by surgery, severe infection, injury, or drugs. In cases of acute kidney injury, serum creatinine levels and estimated glomerular filtration rate (eGFR) may not reliably assess kidney function. For patients at risk of chronic kidney function decline (e.g., age > 60 years, diabetes, or chronic hypertension), eGFR should be estimated by laboratory tests. Factors that may increase the risk of NSF include repeated use or use of gadolinium-based contrast agents (GBCAs) at doses higher than recommended, and the degree of renal impairment at the time of exposure. Record the specific GBCA used by the patient and its dose. For patients at high risk of NSF, do not exceed the recommended ProHance dose and allow sufficient time for drug clearance before re-administration. For patients undergoing hemodialysis, the physician may consider initiating hemodialysis immediately after gadolinium-based contrast agent injection to facilitate contrast agent clearance. The role of hemodialysis in preventing renal systemic fibrosis (NSF) is not well understood. The possibility of adverse reactions should always be considered, including serious, life-threatening, or fatal anaphylactic or cardiovascular reactions, or other specific reactions, especially in patients with a known history of clinical hypersensitivity or a history of asthma or other allergic respiratory conditions. FDA Pregnancy Risk Category: C/Risk cannot be ruled out. There is a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. If this drug is used during pregnancy, there is a possibility of fetal harm; however, the potential benefits may outweigh the potential risks. For more complete data on drug warnings for gadolinium (19 in total), please visit the HSDB records page.

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Pharmacodynamics
Gadolinium affects proton relaxation time, thus affecting magnetic resonance imaging (MRI) signals. Signal intensity is affected by the dose and relaxation rate of the gadolinium molecule. As with all gadolinium-based contrast agents, the relaxation rate of gadolinium decreases with increasing magnetic field strength (0.2–3.0 T) used in clinical MRI. Blood-brain barrier disruption or vascular abnormalities can lead to gadolinium accumulation at lesion sites such as tumors, abscesses, and subacute infarctions. The pharmacokinetics of gadolinium in various lesions are not fully understood.

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Gadolinium is a commonly used magnetic resonance imaging (MRI) contrast agent used to monitor the real-time distribution of molecules in the brain, thereby visualizing the volume of drug diffusion in different brain structures. [1]
This study explored gadolinium as a tool to enhance the transduction efficiency (distribution) of adeno-associated virus (AAV) vectors (particularly rAAV1) in the rat hippocampus for gene delivery applications. [1]
The study concluded that co-infusion of gadolinium with rAAV1 is a safe method to increase the distribution of viral vectors in the hippocampus without adverse effects on function, which can reduce the number of injection sites required to target more brain regions in animal models. [1]

C₁₇H₂₈GDN₄O₇

557.68

558.12

120066-54-8

Gadoteridol pentahydrate

60714

White to off-white solid powder

668.2ºC at 760 mmHg

>225ºC

357.9ºC

1.04E-20mmHg at 25°C

1

11

5

29

471

0

DPNNNPAKRZOSMO-UHFFFAOYSA-K

InChI=1S/C17H32N4O7.Gd/c1-14(22)10-18-2-4-19(11-15(23)24)6-8-21(13-17(27)28)9-7-20(5-3-18)12-16(25)26;/h14,22H,2-13H2,1H3,(H,23,24)(H,25,26)(H,27,28);/q;+3/p-3

2-[4,7-bis(carboxylatomethyl)-10-(2-hydroxypropyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+)

SQ-32692SQ32692 Gd-HP-DO3A

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 280 mg/mL (~502.08 mM)
DMSO :< 1 mg/mL

Solubility in Formulation 1: 100 mg/mL (179.31 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)