Drug Metabolism and Bioanalysis Letters Formerly: Drug Metabolism Letters - Volume 15, Issue 2, 2022

Coronaviruses cause disease in humans and animals. In 2019 a novel coronavirus was first characterized in Wuhan, China causing acute respiratory disease and designating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19. The COVID-19 spread to all cities of China and in 2020 to the whole world. Patients with COVID-19 may recover without medical treatment. However, some patients need medical care. The Cytochrome p450s (CYP450s) are a large superfamily of enzymes that catalyze the metabolism of endogenous substrates and xenobiotics. CYP450s catalyze the biotransformation of 80% of the drug in clinical use. The CYP450 is present in liver, lungs, intestine and other tissues. COVID-19 has been reported to decrease the activity of certain isoforms of CYP450s in an isoform specific manner. Furthermore, the COVID-19 infection decreases the liver functions including the drug clearance or detoxification medicated by the CYP450s. The healthcare providers should be aware of this disease-drug interaction when prescribing drugs for the treatment of COVID-19 and other comorbidities.

Objective: The mechanism-based inhibition of macrolide antibiotics, such as erythromycin and clarithromycin, and piperine on testosterone 6β-hydroxylation activities by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared. Methods: 6β-Hydroxy testosterone was determined by high-performance liquid chromatography. Results: Although preincubation with erythromycin and clarithromycin decreased CYP3A4- mediated testosterone 6β- hydroxylation in a time-dependent manner, and the estimated maximum inactivation rate constant (k inact) and the inactivation rate constant reaching half of k inact (K i) for erythromycin were approximately 1/2 and 1/5, respectively, of those for clarithromycin. Obvious preincubation time-dependent inhibition of erythromycin against CYP3A5 and CYP3A7 was not observed. Piperine exhibited preincubation time-dependent inhibition and the calculated K i and k inact values for CYP3A4 were approximately 1/7 and 1/2, respectively, of those for CYP3A5. Conclusion: It is speculated that the preincubation-dependent inhibition by piperine would be more potent in CYP3A5 non-expressors than CYP3A5-expressors.

Background: Neurological complications are most likely to be fatal and cause loss of ability to function or care for self. These include Alzheimer’s disease and cognitive impairment. The main aim of the review is to determine the effects of various drugs and their cognitive risk with the need to opt for herbal therapy as an adjuvant in treating neurological conditions like Alzheimer’s disease with lesser-known side effects. Methods: Involved a detailed literature survey which was performed through an online database, such as Science Direct, Google Scholar, Scopus, Cochrane, and PubMed. The study included randomized trials and original research conducted by herbal supplements on animal models to assess the expression of upregulation of signalling pathways. Various studies involved in treating dementia, neurological disorders, Alzheimer disease, and cognitive dysfunction were included. Results: Found that various studies involved plant-based products were showing improvement in prevention of disease and signalling pathways with lesser-known side effects. Conclusion: It was observed that plant-based products play a major role in the prevention of neurological complications. Herbal medicines could most suitably prevent Alzheimer’s risk with less known side effects in contrast with the existing treatment patterns. However, to improve the utility of herbal medicines, more evidences from in vitro, in vivo, and clinical trials need to be addressed.

The use of pharmacotherapy for improving healthcare in society is increasing. A vast majority of patients have either received subtherapeutic treatment (which could result from low pharmacokinetics) or experienced adverse effects due to the toxic levels of the drug. The medicines used to treat chronic conditions, such as epilepsy; cardiovascular diseases; oncological, neurological, and psychiatric disorders, require routine monitoring. New targeted therapies suggest an individualized treatment that can slowly move practitioners away from the concept of a one-sizefits- all-fixed-dosing approach. Therapeutic drug use can be monitored based on pharmacokinetic, pharmacodynamic, and pharmacometric methods. Based on the experiences of therapeutic drug monitoring of various agents across the globe, we can look ahead to the possible developments of therapeutic drug monitoring in India.

Background: Migraine is a neurological disorder and is accompanied by different painful episodes. Hence, the maintenance of a steady-state concentration of drugs can be beneficial for patients suffering from migraine. The present investigation focuses on the development of nano lipid carriers (NLCs) loaded with transdermal patches of rizatriptan benzoate to sustain the effect of the drug for the enhancement of therapeutic effects. Methods: Stearic acid and peanut oil were used to make the NLCs. A central composite design was employed to observe the effect of formulation factors like solid lipid ratio, phase volume ratio, and concentration of surfactants on the formation of nanoparticles. The effects were evaluated for the responses like particle size and entrapment of the drug in the nanocarriers. The optimized formulation was subjected to compatibility, thermal, surface characteristics, and surface morphology studies. The optimized formulation was dispersed in HPMC 15CPS and PVP K30 polymer matrix, and the transdermal patch was evaluated for its mechanical properties, drug release study, and skin irritation study. Results: The experimental design was suitable to produce nanosized stable lipid carriers of the drug with high drug entrapment. The drug and excipients were found to be compatible. The thermal and surface characteristics study proved the high loading of drugs in the nanoparticles. The surface morphology study showed the formation of irregular-shaped NLCs. The transdermal patch had good mechanical properties. The ex vivo study of the formulated patch showed a sustained release of the drug over 24h. No skin irritation was reported from the transdermal patch. Conclusion: Therefore, it can be concluded that the nanoparticles loaded transdermal patch of rizatriptan benzoate can be promising in controlling the divergent phases of migraine.

Background: Identification of clinical Drug-Drug Interaction (DDI) risk is an important aspect of drug discovery and development owing to poly-pharmacy in present-day clinical therapy. Drug Metabolizing Enzymes (DME) play important roles in the efficacy and safety of drug candidates. Hence, the evaluation of a New Chemical Entity (NCE) as a victim or perpetrator is very crucial for DDI risk mitigation. ZY12201 (2-((2-(4-(1H-imidazol-1-yl) phenoxy) ethyl) thio)-5-(2- (3, 4-dimethoxy phenyl) propane-2-yl)-1-(4-fluorophenyl)-1H-imidazole) is a novel and potent Takeda-G-protein-receptor-5 (TGR-5) agonist. ZY12201 was evaluated in-vitro to investigate the DDI liabilities. Objective: The key objective was to evaluate the CYP inhibition potential of ZY12201 for an opportunity to use it as a tool compound for pan CYP inhibition activities. Methods: In-vitro Drug-Metabolizing Enzyme (DME) inhibition potential of ZY12201 was evaluated against major CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5), Aldehyde Oxidase (AO), Monoamine Oxidase (MAO), and Flavin-containing Monooxygenase (FMO) in human liver cytosol/mitochondrial preparation/microsomes using probe substrates and Liquid Chromatography with tandem Mass Spectrometry (LC-MS-MS) method). Results: It was found that the study conducted on ZY12201 at 100 μM ZY12201 showed a reduction in the metabolism of vanillin (AO probe substrate), tryptamine (MAO probe substrate), and benzydamine (FMO probe substrate) by 49.2%, 14.7%, and 34.9%, respectively. ZY12201 Ki values were 0.38, 0.25, 0.07, 0.01, 0.06, 0.02, 7.13, 0.03 and 0.003 μM for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5 (substrate: testosterone) and CYP3A4/5 (substrate: midazolam), respectively. Time-dependant CYP inhibition potential of ZY12201 was assessed against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5, and no apparent IC50 shift was observed. Conclusion: ZY12201, at 100 μM concentration, showed low inhibition potential of AO, MAO, and FMO. ZY12201 was found as a potent inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 while moderately inhibiting CYP2E1. Inhibition of CYP1A2, CYP2B6, CYP2C19, and CYP2E1 by ZY12201 was competitive, while the inhibition of CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5 was of mixed-mode. ZY12201 is a non-time-dependent inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. In summary, the reported Ki values unequivocally support that ZY12201 has a high potential to inhibit all major CYP isoforms. ZY12201 can be effectively used as a tool compound for in-vitro evaluation of CYP-based metabolic contribution to total drug clearance in the lead optimization stage of drug discovery research.