Current Drug Metabolism - Volume 22, Issue 9, 2021

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John’s wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.

Drug metabolism studies play a critical role in the optimization of the therapeutic efficacy of newer drug candidates. Many drug candidates and drugs were withdrawn from the pre-clinical/clinical stage or market due to the poor metabolic profiles. The poor metabolic profiles may make the clinical candidates/drugs inactive or toxic. Therefore, it is necessary to optimize the metabolic profiles at the initial phase of drug discovery and development processes. Recently, molecular modeling approaches were found to be useful in the optimization of metabolic profiles of clinical candidates. The molecular modeling approaches were employed in the identification of various metabolic profiles. In the present study, the current status of the research work on drug metabolism based on molecular modeling methodologies has been reviewed. The basics of drug metabolism and its importance in the physiological process of the human body have been described. Moreover, the involvement of molecular modeling approaches like pharmacophore- based modeling, QSAR, molecular docking, virtual screening, quantum chemical analysis, molecular dynamics, etc., in predicting metabolic profiles of therapeutic agents is analyzed. The present review provides computational insights in the prediction of substrate specificity, metabolic activity, SOM, metabolites, toxicity, etc., on cytochrome P450-mediated drug metabolism. The study may help the researchers to design novel drug candidates for the various classes of therapeutic targets with efficient metabolic profiles.

Background: In recent years, the significance of cytochrome P450 enzymes (CYPs) has expanded beyond their role in the liver. Factors such as genetics, environmental toxins, drug biotransformation and underlying diseases mediate the expression of these enzymes. Among the CYP enzymes, CYP2E1, a well-recognized monooxygenase enzyme involved in the metabolism of various endogenous and exogenous substances, plays a crucial role in the brain concerning the development of Parkinson’s disease. The expression of CYP2E1 varies in different brain regions making certain regions more vulnerable than others. CYP2E1 expression is inducible which generates tissuedamaging radicals leading to oxidative stress, mitochondrial dysfunction and ultimately neurodegeneration. Objective: Less is understood about the role of CYP2E1 in the central nervous system, therefore the purpose of the study was to investigate the relationship between the expression and activity of CYP2E1 enzyme relevant to Parkinson’s disease and to identify whether an increase in the expression of CYP2E1 is associated with neurodegeneration. Methods: The objectives of the study were achieved by implicating an unsystematic integrative literature review approach in which the literature was qualitatively analysed, critically evaluated and a new theory with an overall view of the mechanism was presented. Results: The contribution of CYP2E1 in the development of Parkinson’s disease was found to be significant as the negative effects of CYP2E1 overshadowed its protective detoxifying role. Conclusion: Overexpression of CYP2E1 seems detrimental to dopaminergic neurons, therefore, to overcome this, a synthetic biochemical is required, which paves the way for further research and development of valuable biomolecules.

Background: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Methods: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized. Results: Hypoxia can up or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drugmetabolizing enzymes and transporters. Conclusion: The findings of this review indicated that miRNA plays a key role in the expression changes of drugmetabolizing enzymes and transporters under hypoxia.

Clays have been used in various health care products, including drug delivery systems. Advanced formulations have been investigated to take full advantage of clays or clay-based materials. The remarkable properties of clays, such as high adsorption, high surface area and high ion exchange capacities, provide an ideal system for the delivery of poorly water-soluble drugs. Currently, there is still limited information on the classification and discussion of clay-based formulations for poorly water-soluble drugs. This review aims to describe efficient delivery systems that use clay as the main excipient in formulations. More details regarding the strategies of using clays in formulations as well as fabrication methods will be discussed. Moreover, combinations with other excipients in hybrid formulations will also be mentioned and the efficacy of these systems will be evaluated. The recent studies on claybased formulations for poorly water-soluble drugs provide fundamental approaches and prospects to be applied in drug development.

Background: Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase in FGAR is attributed to the inhibition of the enzyme FGAR amidotransferase (FGAR-AT) that catalyzes the ATP-dependent amidation of FGAR to formylglycinamidine ribonucleotide (FGAM). While perturbation of this pathway resulting from GA therapy has long been recognized, no study has reported systematic quantitation and analyses of FGAR in plasma and tumors. Objective: Herein, we aimed to evaluate the efficacy of our recently discovered tumor-targeted GA prodrug, GA-607 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate), and demonstrate its target engagement by quantification of FGAR in plasma and tumors. Methods: Efficacy and pharmacokinetics of GA-607 were evaluated in a murine EL4 lymphoma model followed by global tumor metabolomic analysis. Liquid chromatography-mass spectrometry (LC-MS) based methods employing the ion-pair chromatography approach were developed and utilized for quantitative FGAR analyses in plasma and tumors. Results: GA-607 showed preferential tumor distribution and robust single-agent efficacy in a murine EL4 lymphoma model. While several metabolic pathways were perturbed by GA-607 treatment, FGAR showed the highest increase qualitatively. Using our newly developed sensitive and selective LC-MS method, we showed a robust >80- and >10- fold increase in tumor and plasma FGAR levels, respectively, with GA-607 treatment. Conclusion: These studies describe the importance of FGAR quantification following GA therapy in cancer and underscore its importance as a valuable pharmacodynamic marker in the preclinical and clinical development of GA therapies.

Background: Recently, the combination of Traditional Chinese Medicine (TCM) formulae and other drugs has been used frequently in clinical practice, while the possibility of herb-drug interaction (HDI) risk remains a challenge. Since metabolic enzymes mediate the majority of drug interactions, evaluating the effects of formulae on metabolic enzymes is therefore instructive for the rational formulation of drug delivery plans. Objective: Herein, we are devoted to estimating the effects of Zhenwu detection (ZWD) on activities and mRNA expression of 7 cytochrome P450 (CYP450) isoenzymes in chronic heart failure (CHF) rats. Methods: The CHF rats were replicated by coronary artery ligation and were randomly divided into sham operation group, model group, ZWD low- (2.188 g/kg), middle- (4.375 g/kg), and high- (8.750 g/kg) dose groups, n=6. After 8 weeks, rats were administrated with ZWD and normal saline (NS) for four weeks, and the mixed solution of 7 probe drugs (1 mL/kg) was subsequently injected into 30 rats through the caudal vein after the last administration. Pharmacokinetic parameters and mRNA expression of 7 probe drugs were measured by using UPLC-MS/MS and RT-qPCR, respectively. Results: Activities and mRNA expression of CYP1A2, CYP2B1, CYP2C6, CYP2C11, CYP3A1 were inhibited in CHF rats, and ZWD could reverse this effect except for CYP2B1. Conclusion: Overall, these findings underscore that for CHF patients, the HDI should be taken into consideration when ZWD is used on its own or combined with drugs meditated by CYP1A2 (CYP1A2 in rats), CYP2C9 (CYP2C6 in rats), CYP2C19 (CYP2C11 in rats) and CYP3A4 (CYP3A1 in rats). Furthermore, since the apparent volume of distribution (Vd) of amodiaquine, dextromethorphan and bupropion has been proved to be far greater than the total volume of body fluids, we speculate that the dose adjustment and potential organotoxicity of these substrates may need further consideration.