Drug–Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes

Klomp, Florian; Wenzel, Christoph; Droździk, Marek; Oswald, Stefan

doi:10.3390/pharmaceutics12121201

Cited by 38 publications

(25 citation statements)

References 177 publications

(36 reference statements)

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“…Whereas derivatives ( 4c , 4d , 6e, and 6g ) are considered as perpetrators and expected to have in vivo DDIs with the drugs undergoing CYP1A2-mediated metabolism such as cardiovascular drugs (propranolol and verapamil), antipsychotics (clozapine and olanzapine), antidepressants (duloxetine, agomelatine, and mirtazapine), NSAIDs (phenacetin), phosphodiesterase inhibitors (theophylline), and CNS stimulants (caffeine) [ 56 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

et al. 2021

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The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX‑2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff’s bases as: antibacterial, COX‑2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

et al. 2021

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“…Although some studies have showed that P450 metabolic activity of a drug could be frequently different in the gut and the liver ( Choe et al, 2017 ; Kapetas et al, 1208 ; Kurucz et al, 2019 ; Klomp et al, 2020 ), the metabolic parameter of saxagliptin by intestinal CYP3A4 was considered comparable to hepatic CYP3A4 in this PBPK-DO model. f a and ASF were incorporated into this model to optimize PK peak time of saxagliptin and scale the effective permeability 4, 6 , which greatly improved prediction performance.…”

Section: Discussionmentioning

confidence: 99%

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

Li¹,

Liu

et al. 2021

Front. Pharmacol.

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We aimed to develop a physiological-based pharmacokinetic and dipepidyl peptidase 4 (DPP-4) occupancy model (PBPK-DO) characterized by two simultaneous simulations to predict pharmacokinetic (PK) and pharmacodynamic changes of saxagliptin and metabolite M2 in humans when coadministered with CYP3A4 inhibitors or inducers. Ketoconazole, delavirdine, and rifampicin were selected as a CYP3A4 competitive inhibitor, a time-dependent inhibitor, and an inducer, respectively. Here, we have successfully simulated PK profiles and DPP-4 occupancy profiles of saxagliptin in humans using the PBPK-DO model. Additionally, under the circumstance of actually measured values, predicted results were good and in line with observations, and all fold errors were below 2. The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin.

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“…In addition, age, pathologies, and physiological conditions like pregnancy must be considered. Therefore, further research on the relationships of the structure that might maintain and/or improve antimicrobial potency with an adequate safety profile should continue to produce improved molecules [ 5 , 44 , 78 ].…”

Section: Structure-activity Relationship (Sar) Of Quinolonesmentioning

confidence: 99%

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

et al. 2021

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Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the quinolones class of antimicrobials one of the most used in inpatients and outpatients. Initially discovered during the search for improved chloroquine-derivative molecules with increased anti-malarial activity, today the quinolones, intended as antimicrobials, comprehend four generations that progressively have been extending antimicrobial spectrum and clinical use. The quinolone class of antimicrobials exerts its antimicrobial actions through inhibiting DNA gyrase and Topoisomerase IV that in turn inhibits synthesis of DNA and RNA. Good distribution through different tissues and organs to treat Gram-positive and Gram-negative bacteria have made quinolones a good choice to treat disease in both humans and animals. The extensive use of quinolones, in both human health and in the veterinary field, has induced a rise of resistance and menace with leaving the quinolones family ineffective to treat infections. This review revises the evolution of quinolones structures, biological activity, and the clinical importance of this evolving family. Next, updated information regarding the mechanism of antimicrobial activity is revised. The veterinary use of quinolones in animal productions is also considered for its environmental role in spreading resistance. Finally, considerations for the use of quinolones in human and veterinary medicine are discussed.

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Drug–Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes

Cited by 38 publications

References 177 publications

Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

Biological Effects of Quinolones: A Family of Broad-Spectrum Antimicrobial Agents

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