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Repaglinide is an antidiabetic drug in the class of medications known as meglitinides, and was invented in 1983. It is sold by Novo Nordisk under the name of Prandin in the U.S., GlucoNorm in Canada, Surepost in Japan, Repaglinide in Egypt by EIPICO, and NovoNorm elsewhere. In Japan it is produced by Dainippon Sumitomo Pharma.

Uses

Repaglinide is used for diabetes mellitus type 2.

Adverse events

Hypoglycemia, diarrhea, nausea, rash and weight gain,

Drug interactions

Repaglinide is a major substrate of CYP3A4 and should not be administered concomitantly with gemfibrozil, clarithromycin or azole antifungals such as itraconazole or ketoconazole^{[citation needed]}. Administration of both repaglinide and one or more of these drugs results in an increase in plasma concentration of repaglinide and may lead to hypoglycemia. Repaglinide should not be combined with sulfonylurea, because they have the same mechanism of action.

Contraindications

Type 1 diabetes, severe liver disease, pregnancy and lactation are contraindications.

Comparisons with other drugs for type 2 diabetes

A study funded by Novo Nordisk, the U.S. distributor for Repaglinide, compared their product with Nateglinide in "A randomized, parallel-group, open-label, multicenter 16-week clinical trial".^[1] They concluded that the two were similar, but "repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA1c and FPG values after 16 weeks of therapy." However, 7 percent of the Repaglinide patients "had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide"; this difference was not statistically significant. They also cited a 1-year study that concluded that "repaglinide had similar efficacy to glyburide."

Mechanism of Action

Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion.

History

Precursor drugs to repaglinide were invented in late 1983 by scientists at Dr Karl Thomae GmbH, a German drug manufacturer located at Biberach an der Riß in southern Germany which was acquired by Boehringer Ingelheim in 1990. The drug that became repaglinide was later licensed by Boehringer to Novo Nordisk, which filed an Investigational New Drug application for the compound with the Food and Drug Administration (FDA) in April 1992. Novo Nordisk filed its New Drug Application (NDA) for Prandin in July 1997 and it was quickly approved, gaining FDA approval in December 1997. The drug was the first of the meglitinide class. It was branded Prandin because its quick onset and short duration of action concentrates its effect around meal time (the prandium was the Roman meal which is comparable to the modern lunch).

Intellectual property

After several attempts to file for U.S. patent protection, a filing was made in March 1990 which eventually became U.S. Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000). After filing its NDA for repaglinide in 1997, Novo Nordisk applied for patent extension under the Hatch-Waxman Act. This process, called patent term restoration, allows drug patents to be extended based on the time that a drug spent in clinical trials and in the approval process. Previously it had been decided by the U.S. Patent and Trademark Office that the expiration date of U.S. Patents 5,216,167 and 5,312,924 would be 5 September 2006. In February 2001 Prandin's patent life was extended to 14 March 2009 in response to Novo Nordisk's patent term restoration application, with U.S. Patent 5,216,167 having been reissued as RE37035.^[2]

Prior to the end of repaglinide's patent term, Novo Nordisk obtained a new patent, U.S. Patent 6,677,358 (January 2004), covering the combination therapy of repaglinide together with the generic anti-diabetic drug metformin. This new patent was due to expire June 2018. In January 2011, a federal court ruled Novo Nordisk's new patent invalid on the grounds of obviousness, and unenforceable on the grounds of inequitable conduct on the part of Novo Nordisk's patent attorneys.^[3]

Supply

Repaglinide is available in 0.5 mg, 1 mg and 2 mg tablets.

References

^ Rosenstock, Julio Rosenstock; Hassman, David R.; Madder, Robert D.; Brazinsky, Shari A.; Farrell, James; Khutoryansky, Naum; Hale, Paula M. (June 2004), "Repaglinide Versus Nateglinide Monotherapy: A randomized, multicenter study", Diabetes Care (American Diabetes Association) 27 (6): 1265–1270, doi:10.2337/diacare.27.6.1265, retrieved 2014-11-20
^ "Details for Patent: RE37035".
^ Frankel, Alison (2011-01-27). "Judge Finds Novo Nordisk Diabetes Drug Patent Invalid and Unenforceable, Questions In-House Patent Lawyer's Conduct". Retrieved 2011-02-05.

External links

Prandin's label
Prandin Repaglinide Tablets (manufacturer's website)
RE37035, the reissued U.S. Patent 5,216,167
U.S. Patent 5,312,924
U.S. Patent 6,143,769
U.S. Patent 6,677,358

UpToDate Contents

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1. 2型糖尿病の治療のためのジペプチジルペプチダーゼ4（DPP-4）阻害剤 dipeptidyl peptidase 4 dpp 4 inhibitors for the treatment of type 2 diabetes mellitus
2. 糖尿病の治療におけるスルホニル尿素およびメグリチニド sulfonylureas and meglitinides in the treatment of diabetes mellitus
3. 透析前慢性腎臓病または末期腎不全を伴う2型糖尿病患者における高血糖のマネージメント management of hyperglycemia in patients with type 2 diabetes and pre dialysis chronic kidney disease or end stage renal disease
4. 成人の2型糖尿病における血糖の初期マネージメント initial management of blood glucose in adults with type 2 diabetes mellitus
5. 2型糖尿病における持続性高血糖のマネージメント management of persistent hyperglycemia in type 2 diabetes mellitus

English Journal

Characterization, quantification and stability of differently prepared amorphous forms of some oral hypoglycaemic agents.

Chadha R, Bhandari S, Arora P, Chhikara R.SourceUniversity Institute of Pharmaceutical Sciences, UGC Center of Advanced Study, Panjab University , Chandigarh-160014 , India.
Pharmaceutical development and technology.Pharm Dev Technol.2013 Mar;18(2):504-14. doi: 10.3109/10837450.2012.723719. Epub 2012 Oct 15.
The study deals with the investigation of possible differences induced in the physicochemical properties within the amorphous forms prepared by different methods. Enthalpy of solution measured by solution calorimetry was utilized to highlight the differences prevailing within the amorphous forms and
PMID 23061933

Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes.

Kudo T, Hisaka A, Sugiyama Y, Ito K.SourceMusashino University, Research Institute of Pharmaceutical Sciences, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. k-ito@musashino-u.ac.jp.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2013 Feb;41(2):362-71. doi: 10.1124/dmd.112.049460. Epub 2012 Nov 8.
The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic upt
PMID 23139378

Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips.

Baudoin R, Prot JM, Nicolas G, Brocheton J, Brochot C, Legallais C, Benech H, Leclerc E.SourceLaboratoire de Biomécanique et Bio ingénierie , CNRS UMR 7338, Université de Technologie de Compiègne , France.
Xenobiotica; the fate of foreign compounds in biological systems.Xenobiotica.2013 Feb;43(2):140-52. doi: 10.3109/00498254.2012.706725. Epub 2012 Jul 25.
We present characterization of the metabolic performance of human cryopreserved hepatocytes cultivated in a platform of parallelized microfluidic biochips. The RTqPCR analysis revealed that the mRNA levels of the cytochromes P450 (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) were reduced after the a
PMID 22830982

Japanese Journal

Preparation, Characterization and in Vivo Evaluation of Antihyperglycemic Activity of Microwave Generated Repaglinide Solid Dispersion

Zawar Laxmikant Ramvallabh,Bari Sanjay Baburao
Chemical and Pharmaceutical Bulletin 60(4), 482-487, 2012
… The influence of microwave technology on the in vitro dissolution rate and in vivo antihyperglycemic activity of a poorly water soluble drug, repaglinide (RG) was studied. …
NAID 130001852439

薬物の体内動態に及ぼすＳＬＣＯ１Ｂ１遺伝子多型の影響と臨床的意義

高根浩
YAKUGAKU ZASSHI 131(11), 1589-1594, 2011
… Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). …
NAID 130001491113

Electrochemical characterization of repaglinide and its determination in human plasma using liquid chromatography with dual-channel coulometric detection

JIROVSKY David,BARTOSOVA Zdenka,SKOPALOVA Jana,MAIER Vitezslav
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 878(31), 3243-3248, 2010-12-01
NAID 10028044348

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リンク元

「レパグリニド」

Repaglinide
Systematic (IUPAC) name
	(S)-(+)-2-ethoxy-4-[2-(3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino)-2-oxoethyl]benzoic acid
Clinical data
Trade names	Prandin
AHFS/Drugs.com	monograph
MedlinePlus	a600010
Licence data	EMA:Link, US FDA:link
Pregnancy; category	AU: C; US: C (Risk not ruled out);
Legal status	AU: Prescription Only (S4); CA: ℞-only; UK: Prescription-only (POM); US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	56% (oral)
Protein binding	>98%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4-mediated)
Half-life	1 hour
Excretion	Fecal (90%) and renal (8%)
Identifiers
CAS Registry Number	135062-02-1
ATC code	A10BX02
PubChem	CID 65981
DrugBank	DB00912
ChemSpider	59377
UNII	668Z8C33LU
KEGG	D00594
ChEMBL	CHEMBL1272
Chemical data
Formula	C27H36N2O4
Molecular mass	452.586 g/mol
	SMILES O=C(O)c1ccc(cc1OCC)CC(=O)N[C@H](c2ccccc2N3CCCCC3)CC(C)C;
	InChI InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1 ; Key:FAEKWTJYAYMJKF-QHCPKHFHSA-N ;
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　　[★]

英: repaglinide
商: シュアポスト(大日本住友製薬)
関: グリニド系薬

[1] Rosenstock, Julio Rosenstock; Hassman, David R.; Madder, Robert D.; Brazinsky, Shari A.; Farrell, James; Khutoryansky, Naum; Hale, Paula M. (June 2004), "Repaglinide Versus Nateglinide Monotherapy: A randomized, multicenter study", Diabetes Care (American Diabetes Association) 27 (6): 1265–1270, doi:10.2337/diacare.27.6.1265, retrieved 2014-11-20

[2] "Details for Patent: RE37035".

[3] Frankel, Alison (2011-01-27). "Judge Finds Novo Nordisk Diabetes Drug Patent Invalid and Unenforceable, Questions In-House Patent Lawyer's Conduct". Retrieved 2011-02-05.

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repaglinide