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Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
Drugs with analgesic and moderate anti-inflammatory effectsPropionic acid derivativesIbuprofenKetoprofenFenoprofenFlurbiprofenCarprofenIndoprofenNaproxenOxaprozinFenamic acid derivativesMefenamic acidMeclofenamic acidFlufenamic acidTolfenamic acid
Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
According to recent FDA guidelines, if >10% of a parent drug forms a metabolite, that metabolite will need to undergo separate toxicity testing. For this purpose, large quantities of the drug metabolite is needed (FDA, 2016). Therefore, recent studies highlighted the broad applications of engineered CYPBM3 in the production of human metabolites (Girvan and Munro, 2016). For example, the Munro group engineered CYPBM3 by rational mutagenesis to facilitate the binding of the proton pump inhibitor, omeprazole. The mutations of F87V and A82F resulted in a conformational alternation and a decreased free energy barrier, ultimately changing the substrate recognition. These mutants of CYPBM3 were able to transform omeprazole to the human CYP2C19-type metabolite (Butler et al., 2013). The same group further demonstrated the efficient transformation of several proton pump inhibitors (e.g., lansoprazole, esomeprazole) to human CYP-type metabolites by CYPBM3 F87V/A82F mutants (Butler et al., 2014). In a recent work, a library of CYPBM3 variants carrying multiple mutations that were identified from directed evolutions showed a high oxidation activity for a wide range of drugs. Few of these drugs include, non-steroidal anti-inflammatory drugs/NSAIDs (diclofenac and naproxen), muscle relaxant (chlorzoxazone), antidepressant (amitriptyline), anesthetic, antiarrhythmic drug (lidocaine), and steroid hormones (testosterone). Importantly, CYPBM3 mutants from this library converted diclofenac with 91–100% conversion, and produced human CYP2C9-type and CYP3A4-type metabolites, 4’-hydroxylated and 5’-hydroxylated diclofenac with 34% yield and 47% yield, respectively (Ren et al., 2015). In another recent example, CYPBM3 mutant M11, has been proven to produce human metabolites of fenamic acid NSAIDs including mefenamic acid, meclofenamic acid, and tolfenamic acid (Venkataraman et al., 2014; Capoferri et al., 2016). Mutant M11 was generated by using random mutagenesis and had 90-fold higher initial activities compared with human CYP2D6 (van Vugt-Lussenburg et al., 2007). This mutant was able to synthesize benzylic or aromatic hydroxylation metabolites of the fenamic acid NSAIDs with high substrate conversions and high turnover numbers (2000–6000). Because of the high total turnover numbers, M11 can be used as a biocatalytic tool for large-scale production of fenamic acid metabolites to perform characterization study, activity study, and toxicological evaluation of NSAIDs (Venkataraman et al., 2014). Similarly, mutant M11 was capable of metabolizing anticancer drugs cyclophosphamide and ifosfamide, producing active metabolites. It can also be used for extracellular bioactivation, and for providing a catalytically efficient alternative to liver S9 fraction for toxicity evaluation (Vredenburg et al., 2015). In addition, a set of BM3 mutants, generated using both rational and random mutagenesis, was able to produce human metabolites of 17β-estradiol. This engineered CYPBM3 enzyme can catalyze same reactions as human CYP1A1, CYP1A2, and CYP1B1 with high catalytic efficiency (kcat/Km) and total turnover numbers between 1040 and 1210, producing human metabolites for industrial applications (Cha et al., 2014).
Pharmaceuticals agents for preventing NSAID-induced gastric ulcers: a patent review
Published in Expert Review of Clinical Pharmacology, 2021
Daiane Franco Teixeira, Anamaria Mendonça Santos, Ana Maria Santos Oliveira, José Adão Carvalho Nascimento Júnior, Luiza Abrahão Frank, Marilia Trindade De Santana Souza, Enilton Aparecido Camargo, Mairim Russo Serafini
The in vivo experiments used male Wistar rats with gastric inflammation induced by NSAIDs (derivatives of propionic acid, acetic acid, fenamic acid, biphenyl carboxylic acid, and oxicams). They concluded that the formula would be an effective anti-inflammatory agent.