Gadobutrol

Các tên gọi khác (1) :

gadolinium(III) 2,2',2''-(10-((2R,3S )-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

contrast media

Thuốc Gốc

Small Molecule

CAS: 138071-82-6

ATC: V08CA09

CTHH: C₁₈H₃₁GdN₄O₉

PTK: 604.71

Intravenous gadobutrol is a second-generation extracellular non-ionic macrocyclic GBCA (gadolinium-based contrast agent) used in magnetic resonance imaging (MRI) in adults and children older than 2 years of age. It may help visualize and detect vascular abnormalities in the blood brain barrier (BBB) and central nervous system (CNS). In patients with impaired renal function, gadolinium based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF). A physician should be contacted if symptoms of NSF are encountered, such as dark or red patches on the skin; stiffness in joints; trouble moving, bending or straightening arms, hands, legs or feet; burning, itching, swelling, scaling, hardening and tightening of skin; pain in hip bones or ribs; or muscle weakness. Common adverse reactions that may be experienced include headache, nausea, feeling hot, abnormal taste, and warmth, burning or pain local to the injection site. General precautions should be taken in patients who are pregnant or breastfeeding, or who have a history of allergic reaction to contrast media, bronchial asthma or an allergic respiratory disorder.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₁₈H₃₁GdN₄O₉

Phân tử khối

604.71

Monoisotopic mass

605.133204143

InChI

InChI=1/C18H34N4O9.Gd/c23-12-14(15(25)13-24)22-7-5-20(10-17(28)29)3-1-19(9-16(26)27)2-4-21(6-8-22)11-18(30)31;/h14-15,23-25H,1-13H2,(H,26,27)(H,28,29)(H,30,31);/q;+3/p-3/t14-,15-;/s2

InChI Key

InChIKey=ZPDFIIGFYAHNSK-ZCTZICQLNA-K

IUPAC Name

gadolinium(3+) ion 2-[4,7-bis(carboxylatomethyl)-10-[(2R,3S)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetraazacyclododecan-1-yl]acetate

Traditional IUPAC Name

gadolinium(3+) ion 2-[4,7-bis(carboxylatomethyl)-10-[(2R,3S)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetraazacyclododecan-1-yl]acetate

SMILES

[Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1

Độ hòa tan

3.52e+01 g/l

logP

-9.2

logS

-1.3

pKa (strongest acidic)

1.54

pKa (Strongest Basic)

9.95

PSA

194.04 Å²

Refractivity

141.06 m³·mol^-1

Polarizability

44.15 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

-1

Number of Rings

Bioavailability

Dược Lực Học : Even at low concentrations Gadobutrol can lead to distinct shortening of relaxation times of protons in plasma. At physiological conditions (pH=7, temperature=37°C), and 1.5T, the relaxivity (r1) is 5.2L/(mmol·sec) based on the relaxation times (T1), while the relativity (r2) is 6.1L/(mmol·sec) based on relaxation times (T2). Magnetic field strength has only slight influence on relaxivities. Drug concentration and r1 relaxivity may contribute to a T1 shortening effect, which may improve tissue visualization.

Cơ Chế Tác Dụng : Intravenous gadobutrol is a second-generation extracellular non-ionic macrocyclic GBCA (gadolinium-based contrast agent) used in magnetic resonance imaging (MRI) in adults and children older than 2 years of age. It may help visualize and detect vascular abnormalities in the blood brain barrier (BBB) and central nervous system (CNS). In patients with impaired renal function, gadolinium based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF). A physician should be contacted if symptoms of NSF are encountered, such as dark or red patches on the skin; stiffness in joints; trouble moving, bending or straightening arms, hands, legs or feet; burning, itching, swelling, scaling, hardening and tightening of skin; pain in hip bones or ribs; or muscle weakness. Common adverse reactions that may be experienced include headache, nausea, feeling hot, abnormal taste, and warmth, burning or pain local to the injection site. General precautions should be taken in patients who are pregnant or breastfeeding, or who have a history of allergic reaction to contrast media, bronchial asthma or an allergic respiratory disorder. MRI tissue visualization is dependent, in part, on variations in intensity of radiofrequency signals which occur due to differences in proton density, differences of the spin-lattice or longitudinal relaxation times (T1), and differences in the spin-spin or transverse relaxation times (T2). Gadolinium shortens T1 and T2 relaxation times. Greater signal enhancement is achieved with increased shortening of T1 and T2. The extent to which Gadolinium can shorten T1 and T2 is influenced by concentration in tissue, MRI field strength, and the relative ratio of transverse and longitudinal relaxation times. The recommended dose produced the greatest sensitivity of T1 shortening effect in T1-weighted magnetic resonance sequences. In T2-weighted sequences, the large magnetic moment of gadolinium induced local magnetic field inhomogenenities. At high concentrations used during bolus injections, T2-weighted sequences show a signal decrease.

Dược Động Học :

▧ Absorption :
With normal renal function, the AUC is 1.1 ± 0.1 mmol·h/L.
▧ Volume of Distribution :
Rapid distribution to extracellular space occurs after intravenous administration. After a dose of 0.1mmol/kg body weight, an average plasma level of 0.59 mmol/L was measured 2 minutes post injection, and 0.3mmol/L 60 minutes post injection.
▧ Protein binding :
No particular protein binding is displayed.
▧ Metabolism :
Gadobutrol is not metabolized.
▧ Route of Elimination :
Excreted unchanged via glomerular filtration by the kidneys. Extrarenal elimination is negligible.
▧ Half Life :
1.81 hours (1.33-2.13 hours).
▧ Clearance :
In healthy subjects, renal clearance is 1.1 - 1.7mL/(min·kg). Within 2 hours of intravenous injection more than 50% is eliminated via the urine. Within 12 hours more than 90% of the given dose is eliminated. Clearance was observed to be slightly lower in elderly subjects, when using a 0.1mmol/kg dose. In the pediatric population, the median AUC, clearance and elimination half life was observed to be similar across the age range of 2-17, based on a population pharmacokinetic analysis of 130 pediatric subjects aged 2-17. In children aged 2-6 (n=45) the median AUC of gadobutrol was 0.8 mmol·h/L, the median clearance was 0.13L/hr/kg, and the median elimination half life was 1.75h. In children aged 7-11 (n=39) the median AUC of gadobutrol was 1.0 mmol·h/L, the median clearance was 0.1L/hr/kg, and the median elimination half life was 1.61h. In children aged 12-17 (n=46) the median AUC of gadobutrol was 1.2 mmol·h/L, the median clearance was 0.09 L/hr/kg, and the median elimination half life was 1.65h. Approximately 99% (median value) of the dose was recovered in the urine after 6 hours. A prolonged serum half life of gadobutrol is correlated with a reduction in creatinine clearance. In patients with mild-moderate renal impairment (80>CLCR>30 mL/min) the elimination half life was 5.8 ± 2.4 hours, the AUC was 4.0 ± 1.8 mmol·h/L, and complete recovery from the urine is seen within 72 hours. In patients with severe renal impairment (CLCR<30 mL/min) the elimination half life was 17.6 ± 6.2 hours, the AUC was 11.5 ± 4.3 mmol·h/L, and complete recovery from the urine is seen within 5 days. Physicians may consider the prompt initiation of hemodialysis following gadobutrol administration to aid elimination, in patients who are already receiving hemodialysis. After one dialysis session 68% of the initial dose is removed, after the second session 94%, and after the third session 98%.

Độc Tính : Lethality was observed in rodents after a single intravenous administration of 20 mmol/kg. This represents a dose of at least 2 orders of magnitude higher than the standard single diagnostic dose in humans (0.1 mmol/kg). No carcinogenicity studies have been conducted. No mutagenesis was observed in vitro in reverse mutation tests in bacteria, or in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using Chinese hamster V79 cells. Similarly, no mutagenesis was seen in chromosome abberation tests of human peripheral blood lymphocytes. It was also negative in in-vivo micronucleus tests in mice following a 0.5mmol/kg intravenous injection. No fertility or reproductive impairment was observed in male and female rates given doses 12.2 times human equivalent doses, based on body surface area. Intolerance reactions local to the injection site have been observed in rabbits after paravenous administration, and are associated with the infiltration of inflammatory cells, suggesting the possibility of local irritation if the contrast medium leaks around veins in a clinical setting.

Chỉ Định : For diagnostic use only. Indicated for adults and children age 2 and over for contrast enhancement during cranial and spinal MRI, and for contrast-enhanced magnetic resonance angiography (CE-MRA). Gadobutrol is particularly suited for the detection of very small lesions and for the visualization of tumors that do not readily take up contrast media. It may be a desired agent when the exclusion or demonstration of an additional pathology may influence the choice of therapy or patient management. It may also be suitable for perfusion studies in the diagnosis of stroke, detection of focal cerebral ischemia, and in studies of tumor perfusion.

Tương Tác Thuốc :

Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Lumefantrine Additive QTc-prolongation may occur. Consider alternate therapy or monitor closely for QTc-prolongation.

Liều Lượng & Cách Dùng : Injection, solution - Intravenous - 10 mL single-dose pre-filled disposable syringes, 1 mmol gadobutrol per milliliter
Injection, solution - Intravenous - 10 mL single-dose vials, 1 mmol gadobutrol per milliliter
Injection, solution - Intravenous - 15 mL single-dose pre-filled disposable syringes, 1 mmol gadobutrol per milliliter
Injection, solution - Intravenous - 15 mL single-dose vials, 1 mmol gadobutrol per milliliter
Injection, solution - Intravenous - 7.5 mL single-dose pre-filled disposable syringes, 1 mmol gadobutrol per milliliter
Injection, solution - Intravenous - 7.5 mL single-dose vial, 1 mmol gadobutrol per milliliter

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Bayer HealthCare Pharmaceuticals

Sản phẩm biệt dược : Gadavist
Công ty : Bayer Schering Pharma

Sản phẩm biệt dược : Gadovist

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06703

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D07420

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/50419-325-11

PharmGKB

http://www.pharmgkb.org/drug/PA165958377

Wikipedia

http://en.wikipedia.org/wiki/Gadobutrol

RxList

http://www.rxlist.com/gadavist-drug.htm

Drugs.com

http://www.drugs.com/international/gadavist.html

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