Tolvaptan

Các tên gọi khác (1) :

Samsca

vasopressin receptor antagonists

Thuốc Gốc

Small Molecule

CAS: 150683-30-0

ATC: C03XA01

CTHH: C₂₆H₂₅ClN₂O₃

PTK: 448.941

Tolvaptan is used to treat low blood sodium levels (hyponatremia) associated with various conditions like congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormones (SIADH). FDA approved on May 19, 2009.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₆H₂₅ClN₂O₃

Phân tử khối

448.941

Monoisotopic mass

448.155370383

InChI

InChI=1S/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31)/t24-/m1/s1

InChI Key

InChIKey=GYHCTFXIZSNGJT-XMMPIXPASA-N

IUPAC Name

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Traditional IUPAC Name

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

SMILES

CC1=CC=CC=C1C(=O)NC1=CC(C)=C(C=C1)C(=O)N1CCC[C@@H](O)C2=C1C=CC(Cl)=C2

Độ hòa tan

1.24e-03 g/l

logP

5.35

logS

-5.6

pKa (strongest acidic)

11.76

pKa (Strongest Basic)

-2.1

PSA

69.64 Å²

Refractivity

129.16 m³·mol^-1

Polarizability

48.16 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Ghose Filter

true

Dược Lực Học : Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 receptors.

Cơ Chế Tác Dụng : Tolvaptan is used to treat low blood sodium levels (hyponatremia) associated with various conditions like congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormones (SIADH). FDA approved on May 19, 2009. Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin.

Dược Động Học :

▧ Absorption :
Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan.
▧ Volume of Distribution :
Healthy subjects: 3L/kg; slightly higher in heart failure patients.
▧ Protein binding :
99% bound
▧ Metabolism :
Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive.
▧ Route of Elimination :
Fecal- very little renal elimination (<1% is excreted unchanged in the urine)
▧ Half Life :
Terminal half life, oral dose = 12 hours.
▧ Clearance :
4 mL/min/kg (post-oral dosing).

Độc Tính : The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia.

Chỉ Định : Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and cirrhosis.

Tương Tác Thuốc :

Barbital Barbital is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Bicalutamide CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of tolvaptan. This combination is contraindicated.
Carbamazepine Carbamazepine is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Clarithromycin Clarithromycin is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Clotrimazole CYP3A4 Inhibitors (Moderate) may increase the serum concentration of tolvaptan. Coadministration of a strong CYP3A4 inhibitor with tolvaptan is contraindicated.
Conivaptan CYP3A4 Inhibitors (Strong) such as conivaptan may increase the serum concentration of Tolvaptan. Coadministration of a strong CYP3A4 inhibitor with tolvaptan is contraindicated.
Digoxin Tolvaptan increases serum digoxin concentrations due to competitive inhibition of P-glycoprotein in the liver, intestine, and kidney. P-glycoprotein facilitates digoxin efflux thus inhibition of this protein will increase incidence of adverse effects.
Diltiazem Diltiazem is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Erythromycin Erythromycin is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Etravirine Tolvaptan may experience a decrease in serum concentration. It is recommended to avoid concurrent therapy.
Fluconazole Fluconazole is a moderate inhibitor of CYP3A4 and will considerably increase tolvaptan serum concentrations
Itraconazole Itraconazole is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Ketoconazole Ketoconazole is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan by 82%.
Nefazodone Nefazodone is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Phenytoin Phenytoin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Rifabutin Rifabutin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Rifampicin Rifampin is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Ritonavir Ritonavir is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
Saquinavir Saquinavir is a strong inhibitor of CYP3A4 and will increase serum concentrations of tolvaptan.
St. John's Wort St. John's Wort is a CYP3A4 inducer and will decrease serum concentrations of tolvaptan and ultimately, its clinical effects.
Verapamil Verapamil, a moderate CYP3A4 inhibitor, may increase the serum concentration of Tolvaptan. Concomitant therapy is contraindicated.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Tolvaptan by decreasing its metabolism. Concomitant therapy is contraindicated.

Liều Lượng & Cách Dùng : Tablet - Oral - 15 mg, 30 mg, 60 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Otsuka Pharmaceuticals

Sản phẩm biệt dược : Samsca

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06212

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=443894

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=7848276

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D01213

ChemSpider

http://www.chemspider.com/Chemical-Structure.391976.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/59148-021-50

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/monograph/tolvaptan.html

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