Delving into the Latest Updates on Tolbutamide with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

1-Butyl-3-(p-methylphenylsulfonyl)urea, 1-Butyl-3-(p-tolylsulfonyl)urea, 1-Butyl-3-tosylurea

+ [14]

Target

Kir6.2 x SUR1

Mechanism

Kir6.2 agonists(potassium inwardly rectifying channel subfamily J member 11 agonists), SUR1 inhibitors(Sulfonylurea receptor 1 inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication-

Originator Organization

Pharmacia & Upjohn, Inc.

Active Organization

Changzhou Pharmaceutical Factory Co., Ltd.

Inactive Organization

Pharmacia & Upjohn, Inc.

Pfizer Inc.

Drug Highest PhaseApproved

First Approval Date

US (31 May 1957),

Diabetes Mellitus, Type 2

Regulation-

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Structure

Molecular FormulaC12H18N2O3S

InChIKeyJLRGJRBPOGGCBT-UHFFFAOYSA-N

CAS Registry64-77-7

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

20 Sep 2024·The Journal of Organic Chemistry

Metal-Free Synthesis of Pharmaceutically Relevant Sulfonylureas via Direct Reaction of Sulfonamides with Amides

Article

Author: Banerjee, Biplab ; Dash, Rageshree ; Sati, Rakhi ; Mondal, Sahil ; Hashim, Muhammed ; Nishad, Chandra Shekhar

A metal-free process has been developed for the sustainable synthesis of medicinally important sulfonylureas in one pot via the direct reaction of sulfonamides with amides in green solvent (DMC). The reaction proceeded efficiently at room temperature, and the products were obtained in good to excellent yields. The use of readily accessible, inexpensive, and environmentally benign starting materials and reagents, metal-free mild reaction conditions, wide substrate scope, tolerance to air and moisture, operational simplicity, and good atom economy are the salient features of this reaction protocol. Gram-scale synthesis of antidiabetic drugs tolbutamide and chlorpropamide in excellent yields further revealed the practical utility of this procedure. Additionally, the synthetic value of this straightforward method is showcased by the late-stage modification of drug molecules, including drug-drug conjugation with good yields. Preliminary mechanistic studies indicated the in situ generation of an isocyanate intermediate, which further reacts with sulfonamide to form sulfonylurea. As compared to other related methods reported for sulfonylurea synthesis, the current method obviates the requirement of traditional multistep protocols involving isolation of hazardous isocyanates and avoids the use of toxic phosgene.

01 Sep 2024·Journal of Inorganic Biochemistry

Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan

Article

Author: Zhang, Qinghai ; Glass, Karen C ; Edara, Sreeja ; Deodhar, Shruti ; Maekawa, Keiko ; Singh, Ajit K ; Parikh, Sonia J ; Shah, Manish B

The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

1

News (Medical) associated with Tolbutamide

19 Jul 2022

·healthtechinsider.com

New CGM Device for Type 2 Diabetes

MySugarWatch has pushed the pedal on an awareness campaign for its continuous non-invasive glucose monitor called sugarBEAT. MySugarWatch is the UK licensee of Nemaura Medical, a company specializing in developing wearable diagnostic devices. The company aims to cater to the awareness needs of the people with pre-diabetes and diabetes. The campaign, featured in the DailyMail, is set to reach about 1.2 million people. MySugarWatch aims to eliminate skin-pricks test strips historically used by patients to monitor blood sugar level for Type-2 diabetes patients. Studies show that 3.6 million in the UK suffer from Type-2 Diabetes while a further 12.3 million people are at risk of developing the disorder. MySugarWatch adds to the list of continuous glucose monitoring devices. It monitors your blood sugar level every 5 minutes, providing consistent data. The data is then stored in a dedicated app, which maps the 168 glucose level readings taken during the day. This allows you to identify trends and monitor Time-in-Range right from your phone. The device does require calibration with a finger stick; a reading each morning before eating is recommended. Continuous Glucose Monitoring (CGM) was difficult to achieve so far due to difficulties in procedure including regular needle insertion. CGMs like MySugarWatch that measure interstitial fluid glucose levels do not require a needle prick and easily allows patients to make lifestyle changes based on trends in their blood sugar level. These strategic changes will greatly help patients and healthcare professionals to manage, prevent and even reverse Type-2 pre-diabetes. MySugarWatch, unfortunately, is not for Type-1 diabetes patients, or patients who receive injectable insulin or who are taking sulfonylurea medications (Glibenclamide, Gliclazide, Glimepiride, Glipizide, Tolbutamide). As a result, it’s not completely useful as an “artificial pancreas” component. The product does have CE Mark clearance, but not FDA clearance yet.

100 Deals associated with Tolbutamide

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External Link

KEGG	Wiki	ATC	Drug Bank
D00380	Tolbutamide	V04CA01 A10BB03	DB01124

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	CN	Changzhou Pharmaceutical Factory Co., Ltd.	01 Jan 1982

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03291288 (CTgov)	Phase 1	Medication interactions	32	Midazolam (Part 1: Midazolam Only)	nkzgmvytkg(wqdeidxemb) = vulnhnjnht mnyjwdlpwi (rkfqorgvsb, wvtbjojdxe - yqfpgbznsk) View more	-	19 Mar 2020
NCT03291288 (CTgov)	Phase 1	Medication interactions	32	Pexidartinib+Midazolam (Part 1: Pexidartinib + Midazolam (Cycle 1, Day 1))	nkzgmvytkg(wqdeidxemb) = mcrnufglcr mnyjwdlpwi (rkfqorgvsb, tzduheiphv - prptxyzcpw) View more	-	19 Mar 2020
NCT01185548 (JZAR, CTgov)	Phase 1	Metastatic Solid Tumor \| Advanced cancer \| Lymphoma	4	Tasisulam+Tolbutamide	fcutteovpg(leztghvyhc) = zpvbrkmxwr cypfcyosnd (amqazdutvr, glokodcjln - bcoykrasnq) View more	-	19 Oct 2018
NCT01525628 (CTgov)	Phase 1	Chronic hepatitis C genotype 1	72	BI 207127+pegylated interferon+BI 201335+tolbutamide+midazolam+caffeine+ribavirin (Group A)	fahszxbxch(sadhxakrpu) = xgroyusmyw fbsureiebn (fwieyoqxay, irmodhwxyn - namkxtfnrm) View more	-	10 Jun 2016
NCT01525628 (CTgov)	Phase 1	Chronic hepatitis C genotype 1	72	BI 207127+pegylated interferon+BI 201335+tolbutamide+midazolam+caffeine+ribavirin (Group B)	fahszxbxch(sadhxakrpu) = bnafczypvw fbsureiebn (fwieyoqxay, tbaqphnskh - jorydarfbu) View more	-	10 Jun 2016
NCT00741468 (CTgov)	Phase 1	Medication interactions	18	CYP2D6 probe+Proellex+CYP2C19 probe+CYP2C9 probe+CYP3A4 probe+CYP1A2 probe	kxdzcxetvr(tdbdjyedlk) = plrdiatuyw syyypldluu (mwhnuupilf, spqinokyhl - iopaatenbn) View more	-	22 Aug 2014