Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

Parise-Filho, Roberto; Polli, Michelle Carneiro; Barberato‐Filho, Silvio; García, M J; Ferreira, Elizabeth Igne

doi:10.1590/s1984-82502010000300003

Cited by 10 publications

(6 citation statements)

References 95 publications

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“…Carbamates are used as prodrugs of alcohols and phenols to achieve systemic hydrolytic stability and protection from first-pass metabolism ( 23 ). Carbamates of N -monosubstituted and N, N -disubstituted alcohols are chemically stable against hydrolysis ( 21 ), as are the carbamates of N, N -disubstituted phenols but not as much those of N- monosubstituted phenols ( 21 , 24 ). Examples of carbamate prodrugs whose active substance is alcohol or phenol are irinotecan and bambuterol ( Figure 1 ).…”

Section: Carbamates As Prodrugsmentioning

confidence: 99%

“…Bambuterol belongs to long-acting drugs due to catecholic hydroxyl groups in its structure that are quite resistant to hydrolysis and first-pass metabolism. In the lung tissue, bambuterol is hydrolysed to terbutaline by BChE ( Figure 12 ), and in the liver, it is metabolised to terbutaline under the influence of cytochrome P-450-dependent oxidases ( 24 , 107 , 109 ). Terbutaline is an adrenergic agonist that predominantly stimulates ß-2 receptors to relax the smooth muscle of the bronchus and dilate the airways ( 107 , 108 , 109 ).…”

Section: Carbamates As Prodrugsmentioning

confidence: 99%

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Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents

Matošević

Bosak

2020

Archives of Industrial Hygiene and Toxicology

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Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer’s disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.

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Section: Carbamates As Prodrugsmentioning

confidence: 99%

Section: Carbamates As Prodrugsmentioning

confidence: 99%

Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents

Matošević

Bosak

2020

Archives of Industrial Hygiene and Toxicology

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“…The set of prodrugs (PRO) and parent drugs were selected from reference Parise-Filho et al (12). Regarding the commercially available prodrugs, those classified as classical prodrugs, which were designed in order to improve bioavailability, were randomly selected.…”

Section: Drugs and Prodrugs Selectionmentioning

confidence: 99%

“…Regarding prodrug design strategy, or latentiation method, the main purpose is to modify physicochemical properties of drugs to reduce undesirable pharmacokinetic features, but maintaining drug's intrinsic activity. Thus, the drugs' physicochemical properties can be adjusted through a proper choice of carrier groups in order to increase oral absorption, for example (11,12).…”

Section: Introductionmentioning

confidence: 99%

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

et al. 2014

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-Purpose. Prodrug design is a strategy that can be used to adjust physicochemical properties of drugs in order to overcome pharmacokinetic problems, such as poor oral bioavailability. However, Lipinski´s and Veber´s rules predict whether compounds will have absorption problems even before the design of prodrugs. In this context, our goal was to evaluate the molecular properties which most influenced the absorption process of prodrugs compared to its precursor through exploratory data analysis approach. Methods: A variety of prodrugs and respective precursors were randomly selected and classified by its' percentage of human intestinal absorption. Subsequently, different molecular properties were calculated and hierarchical cluster analysis (HCA) and principal components analysis (PCA) were carried out. Results: According to the findings, antiviral, anti-hypertensive, and antibiotic prodrugs exhibited higher absorption levels than their respective precursors. Also, some relevant descriptors (molecular weight, MW, routable bonds, rot_bonds, hydrogen bond acceptors, HBA_count and polar surface area, PSA), which are included in Lipinski´s and Veber´s rules, influenced the separation process between prodrugs and drugs. Furthermore, other molecular properties, such as polarizability (α) and molar refractivity (MR), were pointed out. Conclusion: Lipinski´s and Veber´s rules proved to be important to design an orally administered drug but other descriptors should be considered by medicinal chemists in the prodrug designing process.

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“…Quando metabolizado pela enzima butirilcolinesterase (BuChE), sofre reação de hidrólise e quando metabolizado pelas oxidases do citocromo P450 sofre oxidação, gerando a terbutalina, metabólito ativo com grande atividade broncodilatadora, sendo por isso, muito utilizado no tratamento de doenças respiratórias (LINDBERG et al, 1989;TUNEK et al, 1988;PARISE-FILHO et al, 2010;BANG et al,1998). A Figura 1 ilustra as vias metabólicas citadas.…”

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Avaliação de fungos e complexos de salen na obtenção do metabólito quiral e ativo terbutalina

Zanão¹

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Enantiomers may interact differently in the organism causing pharmacological sundry effects. For these reason, enantiomeric pure drugs are very important for the pharmaceutical industries. Synthetic models employing chiral reagents, like salen complexes, and biological models using fungi are been very studied in this context. Fungi present as main advantage the fast growing up, low costs and easily application, moreover, their metabolites are produced in huge quantities. Salen complexes are efficient and stable. They have a wide application and the possibility of production of high enantiomeric excess. The aim of this work was to evaluate fungi and salen complex as alternatives to the enantioselective production of terbutaline, the chiral and active metabolite of your prodrug, bambuterol. The analytes' enantioselective separation was done employing high performance liquid chromatography with UV-Vis detector (LC/UV). The method validation and the studies of biotransformation were done using high performance liquid chromatography coupled with mass spectrometry (LC-MS). The resolution of bambuterol and terbutaline by LC/UV was accomplished using the Chirobiotic T column and acetonitrile: methanol (80:20, v/v) + 0.3% formic acid and 0.1% triethylamine as mobile phase at a flow rate of 1.5 mL min -1 and by LC-MS employing the same column and the mobile phase was composed by 96% of methanol in water + 0,2% acetic acid and 0,1% ammonium acetate at a flow rate of 0.1 mL min -1 . The analytes' extraction of the culture medium (Czapek, 2 mL) was done using the dispersive liquid liquid microextraction (DLLME), in the following conditions: dispersive solvent, isopropanol (600 µL); extractor solvent, dichloromethane (50 µL); ionic-pair reagent; di(2-ethylhexyl)phosphate (100 µL); and sodium phosphate buffer (2 mL, pH 7.6). The recoveries were 92% for the bambuterol and estimated in 55% for terbutaline. The method was validated for the analysis of bambuterol in the culture medium and was linear over the concentration range of 500 -17500 ng mL -1 for each enantiomer (r > 0.998). The quantification limit was 500 ng mL -1 . Among the evaluated fungi, none was able to do the biotransformation process of bambuterol at terbutaline in the employed conditions and so do the studies employing asymmetric catalyses. Because the complexity of bambuterol's metabolism for producing terbutaline (hydrolysis and/or oxidation reactions) and the formation of several intermediates before the terbulaline's formation step, the evaluated conditions in this study were not able to produce the chiral active metabolite, terbutaline.

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Prodrugs available on the Brazilian pharmaceutical market and their corresponding bioactivation pathways

Cited by 10 publications

References 95 publications

Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents

Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

Avaliação de fungos e complexos de salen na obtenção do metabólito quiral e ativo terbutalina

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