Canagliflozin

Các tên gọi khác (2) :

1-(Glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylmethyl)benzene
Canagliflozin hydrate

antidiabetic agents

Thuốc Gốc

Small Molecule

CAS: 842133-18-0

CTHH: C₂₄H₂₅FO₅S

PTK: 444.516

Canagliflozin belongs to a new class of anti-diabetic drugs that works by inhibiting the sodium-glucose transport protein (SGLT2). This transport protein is found in the kidney and is responsible for reabsorbing glucose that has been filtered. FDA approved on March 29, 2013.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₂₄H₂₅FO₅S

Phân tử khối

444.516

Monoisotopic mass

444.140672805

InChI

InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1

InChI Key

InChIKey=XTNGUQKDFGDXSJ-ZXGKGEBGSA-N

IUPAC Name

(2S,3R,4R,5S,6R)-2-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol

Traditional IUPAC Name

(2S,3R,4R,5S,6R)-2-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol

SMILES

[H][C@]1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C1=CC=C(C)C(CC2=CC=C(S2)C2=CC=C(F)C=C2)=C1

Độ hòa tan

4.50e-03 g/l

logP

3.52

logS

-5

pKa (strongest acidic)

12.57

pKa (Strongest Basic)

-3

PSA

90.15 Å²

Refractivity

116.14 m³·mol^-1

Polarizability

46.5 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

Dược Lực Học : Canagliflozin binds to SGLT2 more potently (250-times) than SGLT1 in vitro. The 50% inhibitory concentrations (IC50) are 2.2-4.4 nmol/L and 684 - 910 nmol/L for SGLT2 and SGLT1 respectively. Dose dependent decreases in renal threshold for glucose and increases in urinary glucose excretion were observed when single and multiple oral doses were administered to type 2 diabetes patients. Decreases in plasma glucose in a dose-dependent fashion were also noted as early as the first day of administration. When given to healthy and type 2 diabetic patients before a meal, a delay in intestinal glucose absorption and a reduction in postprandial glucose was observed. Canagliflozin does not prolong the QTc interval.

Cơ Chế Tác Dụng : Canagliflozin belongs to a new class of anti-diabetic drugs that works by inhibiting the sodium-glucose transport protein (SGLT2). This transport protein is found in the kidney and is responsible for reabsorbing glucose that has been filtered. FDA approved on March 29, 2013. Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.

Dược Động Học :

▧ Absorption :
The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. Accumulation in plasma has been observed following multiple doses of 100 - 300 mg. Food does not affect the absorption of canagliflozin. Tmax = 1- 2 hours; Cmax = 1059 - 3148 ng/mL; Time to steady state, once daily dose, 100 - 300 mg = 4-5 days; Absolute oral bioavailability = 65%.
▧ Volume of Distribution :
Steady state, single IV infusion, healthy subject = 119 L. This high value suggests that cangliflozin is extensively distributed to tissue.
▧ Protein binding :
>99% protein bound, mainly to albumin. It also binds to alpha-acid glycoprotein. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
▧ Metabolism :
Canagliflozin is hepatically metabolized via O-glucuronidation into two inactive O-glucuronide metabolites. The enzymes that facilitate this process are UGT1A9 and UGT2B4. To a lesser extent (7%), canagliflozin also undergoes oxidative metabolism via CYP3A4. Canagliflozin weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes.
▧ Route of Elimination :
Enterohepatic circulation of canagliflozin was negligible. When a single oral dose is administered to a healthy subject, canagliflozin is eliminated via the following: Feces (41.5%, 7.0%, 3.2% as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively). Urine (33%; 30.5% as O-glucuronide metabolite, <1% as unchanged drug).
▧ Half Life :
The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively.
▧ Clearance :
Mean systemic clearance, healthy subjects, IV administration = 192 mL/min. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.

Độc Tính : Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination.

Chỉ Định : Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Use in type 1 diabetes mellitus patients or in treatment of diabetic ketoacidosis is not recommended.

Tương Tác Thuốc :

Aliskiren Monitor therapy because canagliflozin may enhance aliskiren antihypertensive and hyperkalemic effects.
Digoxin When coadministered with 300 mg canagliflozin, the AUC and mean peak drug concentration of digoxin increased. Monitor concomitant therapy closely.
Phenobarbital Nonselective inducers of UGT enzymes may decrease levels of canagliflozin, thus decreasing efficacy. Consider increase the dose to 300 mg once daily.
Phenytoin Nonselective inducers of UGT enzymes may decrease levels of canagliflozin, thus decreasing efficacy. Consider increase the dose to 300 mg once daily.
Rifampicin Nonselective inducers of UGT enzymes may decrease levels of canagliflozin, thus decreasing efficacy. Consider increase the dose to 300 mg once daily.
Ritonavir Nonselective inducers of UGT enzymes may decrease levels of canagliflozin, thus decreasing efficacy. Consider increase the dose to 300 mg once daily.

Liều Lượng & Cách Dùng : Tablet - Oral - 100 mg, 300 mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Janssen Pharmaceuticals

Sản phẩm biệt dược : Invokana

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB08907

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09592

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/50458-141-30

Wikipedia

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

RxList

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

Drugs.com

http://www.drugs.com/invokana.html

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