Drug Metabolism Letters - Current Issue

Background: Glutathione S-transferases (GSTs) are phase II metabolic enzymes crucial for the metabolism of electrophilic drugs. Additionally, several GST isoforms are involved in protein- protein interaction with mitogen-activated protein kinases (MAPKs), modulating apoptosis pathways. Methods: To assess the potential change of enzymatic activity, we performed a GST enzyme assay with human recombinant GSTM1 in the presence and absence of MAPK8. Recently, GSTM1 has been demonstrated to interact with MAPK8 both in silico and in vitro. The binding interface predicted in silico comprised amino acid residues present on the surface of the protein and a few were deep in the active site of the protein. Results: The experiment demonstrated that the GSTM1 activity was conserved even in the presence of MAPK8 in the assay. Conclusion: The possible alteration in the activity of MAPK8 in this interaction needs to be evaluated in further experiments.

Abstract: The liver plays a crucial role in endogenous metabolic activity and homeostasis of macro and micronutrients. Further, it acts as a metabolic hub in mammals, where the ingested food-derived nutrients and xenobiotics or drugs are metabolized for utilization and/or excretion through its enzymatic and non-enzymatic machinery. Nutritional deficiency, one of the major public health problems, is associated with global disease burden, including pulmonary tuberculosis (PTB) caused by Mycobacterium tuberculosis (Mtb) infection. Though it is a curable and preventable infectious disease, millions of people succumb to death, and people in numbers larger than this are still suffering. This scenario is further complicated by the addition of new cases, disease recurrence, and the emergence of drug-resistant, all of which contribute to the spread of this epidemic. Though the manifestation of TB disease has multiple aetiologies, poor nutritional status and sub-optimal therapeutic concentrations of first-line anti-TB drugs are considered as potential contributors to its widespread prevalence. Among various factors, the pharmacokinetic variability of anti-TB drugs is one of the main causes for sub-optimal therapeutic drug concentration in TB patients, which is influenced by the host’s genetic make-up and nutritional status, besides several others. However, the role of epigenetic changes in hepatic drug metabolic pathways and their transcript levels is largely unexplored. Therefore, in this review, an attempt has been made to understand the role of micronutrient deficiencies with special reference to fat-soluble vitamins, namely vitamin A, D, & E in pulmonary TB, their possible impact on epigenetic changes on the drug-metabolizing pathway genes, thus their expression levels and plausible influence on pharmacokinetic variability of anti-TB drugs, besides discussing the limitations and emerging potential opportunities. Eventually, this would help in developing the host-directed/personalized therapeutic strategies for the elimination of pulmonary tuberculosis (PTB).

Abstract: Cysteine is one of the major intermediate products of cellular amino-acid metabolism. It is a semi-essential amino acid for protein synthesis. Besides, it is also employed in the regulation of major endogenous anti-oxidant molecule i.e., reduced glutathione (GSH). Further, it is a precursor of multiple sulfur-containing molecules like hydrogen sulfide, lanthionine, taurine, coenzyme A and biotin. It is also one of the key molecules for post-translational modifications of various cellular proteins. In physiological conditions, it is employed in the sulfhydration process and plays a key role in the physiology modification of the inflammatory process in various organs, including the neurological system. The catabolism of cysteine is regulated by cysteine dioxygenase enzyme activity. The dysregulated conditions of cysteine and cysteine-associated hydrogen sulfide metabolism are widely employed in the acceleration of the neurodegenerative process. Moreover, the upregulation of cysteine and hydrogen sulfide synthesis occurs via the reverse trans-sulfuration process. This process helps to manage the worsening of a pathological condition of a cellular system. Moreover, it is also employed in the accumulation of homocysteine contents. Further, both cysteine and homocysteine molecules are widely accepted as biomarkers for various types of diseases. Therefore, the targets involved in the regulation of cysteine have been considered as valid targets to treat various disorders like cardiac disease, ischemic stroke, diabetes, cancer, and renal dysfunction.

Background: Linagliptin is prescribed as a dipeptidyl peptidase-4 (DPP-4) inhibitor. Azithromycin is specified as an antibiotic that binds with 23s rRNA of the 50s ribosomal subunit, obstructing the microbial protein synthesis. Our study focuses on the drug-drug interactions of these drugs. Objectives: The purpose of the study is to understand the bioavailability and physicochemical approaches of Linagliptin and Azithromycin interaction mediated through the strength and nature of the complexation. Methods: TheIn vitro assessment of drug interaction was conducted using Ultraviolet-visible spectroscopy (UV/VIS), Ultra-Performance Liquid Chromatography (UPLC), Fourier transform infrared spectroscopy (FT-IR), and Differential scanning calorimetry (DSC), while the Oral Glucose Tolerance Test (OGTT) was performed for theIn vivo assessment of drug interaction in a mouse model. Results: Mild variation in interaction was observed at different pH values at a specific temperature by Job's and Ardon's equations. In UPLC, the drug mixture assessment showed that the area of Linagliptin was 2013793, and the area of Azithromycin was 54631 in 50 mg/l. The height of Linagliptin in the drug mixture was 579234, and that of Azithromycin was 11442. For Azithromycin, the wavelength of 731.02 cm^-1, 993.34 cm^-1, 1379.10 cm^-1, and 1718.58 cm^-1 decreased in the mixture. Also, for Linagliptin, the wavelength 1363.67 cm^-1, 1473.62 cm^-1, and 1718.58 cm^-1 decreased in the drug mixture. The melting endotherm was 125.55°C, melting normalized energy was -3.0 W/mg, and 225.75°C with melting normalized energy of -5.5 W/mg of the drug mixture as indicated by DSC. In the OGTT test, the blood glucose level of Linagliptin decreased in the drug mixture by 13.58 % and 57.25%. Conclusion: Hence, the concomitant administration of Linagliptin and Azithromycin simultaneously might reduce the therapeutic effect of the drug complex.

Background: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family characterized by a long-lasting pharmacological activity that has been attributed to its active metabolite E-6132. Objectives: The aim of this work was to explore enflicoxib biotransformation In vitro in humans, rats and dogs, and to determine its metabolic pathways. Methods: Different In vitro test systems were used, including hepatocytes and liver and non-hepatic microsomes. The samples were incubated with enflicoxib and/or any of its metabolites at 37°C for different times depending on the test system. The analyses were performed by liquid chromatography coupled with either radioactivity detection or high-resolution mass spectrometry. Results: Enflicoxib was efficiently metabolized by cytochrome P-450 into three main phase I metabolites: M8, E-6132, and M7. The non-active hydroxy-pyrazoline metabolite M8 accounted for most of the fraction metabolized in all the three species. The active pyrazol metabolite E-6132 showed a slow formation rate, especially in dogs, whereas metabolite M7 was a secondary metabolite formed by oxidation of M8. In hepatocytes, diverse phase II metabolite conjugates were formed, including enflicoxib glucuronide, M8 glucuronide, E-6132 glucuronide, M7 glucuronide, and M7 sulfate. Metabolite E-6132 was most probably eliminated by a unique glucuronidation reaction at a very low rate. Conclusion: The phase I metabolism of enflicoxib was qualitatively very similar among rats, humans and dogs. The low formation and glucuronidation rates of the active enflicoxib metabolite E-6132 in dogs are postulated as key factors underlying the mechanism of its long-lasting pharmacokinetics and enflicoxib's overall sustained efficacy.

Aims: The study was aimed at exploring the role of Acetyl L-Carnitine supplementation attenuating dementia and degradation of cognitive abilities in Hyperhomocysteinemia induced AD manifestations in the mouse model. Background: Alzheimer’s disease (AD) is a neurological disorder that is marked by dementia, and degradation of cognitive abilities. There is great popularity gained by natural supplements as the treatment for AD, due to the higher toxicities of synthetic drugs. Hyperhomocysteinemia causes excitotoxicity to the cortical neurons, which brought us to the point that amino acids possibly have a role in causing cholinergic deformities, which are an important etiological parameter in AD. Acetyl L-Carnitine a methyl donor with the presence of three chemically reactive methyl groups linked to a nitrogen atom was found to possess neuroprotective activity against experimental models of AD. Objective: The objective of the present investigation was to investigate and evaluate the pharmacological effect of Acetyl L-Carnitine against hyperhomocysteinemia induced Alzheimer’s disease (AD) in the mouse model. Materials and Methods: The animals were divided into normal control (vehicle-treated), HHcy (dl-Homocysteine thiolactone treated) negative control, test group i.e., low dose (50mg/kg, p.o) of acetyl L-carnitine (L-ALC), high dose (100mg/kg,p.o) of acetyl L-carnitine (H-ALC), L-ALC+ SOV (Sodium orthovanadate) and H-ALC+SOV. HHcy was induced by administration of dl-Homocysteine thiolactone (dl-HCT; 1 g/kg, p.o.) on day-1 to day-15 of experimental schedule to all animals except normal control. The changes in the behaviour pattern of the animals due to neuroinflammation, and cholinergic dysfunction were examined in rotarod, novel objective recognition, passive avoidance, elevated plus maze, and morris water maze analysis. Biochemical investigation includes the estimation of total homocysteine (tHcy), Creatinine Kinase (CK), Acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and IL-6 and TNF-α. Results: Supplementation of ALC in mouse considerably lowered the HHcy-induced AD manifestations in the experimental animals. It was found that ALC and SOV successfully diminished the behaviour abnormalities and lessened the Hcy-induced alteration in systemic Hcy levels, CK activity, and cholinergic dysfunction with improved bioenergetics in the Prefrontal cortex of the mice. Conclusion: ALC was found to improve the HHcy-induced cognitive disabilities which was found to be associated with the decreased systemic levels of Hcy, CK, and cholinergic abnormalities. It also combats the oxidative stress-induced neuroinflammation with diminished pro-inflammatory markers in the pre frontal cortex. The outcomes collectively indicate ALC's potential to be used as a supplementation in the pharmacotherapy of AD.

A typographical error appeared in the author’s name of the article entitled “Inhibitory Effect of Codeine on Sucrase Activity“ by Dariush Minai-Tehrani, Saeed Minoui, Marzie Sepehre, Zohre Sharif-Khodai, Tooka Aavani, Drug Metabolism Letters, 2009; 3(1): 58-60. [1]. Details of the error and a correction are provided here. The fourth author's name in this article was misspelled. Hence it should be read as "Zohreh Sharifkhodaei" as per the request of the author. We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/93132/article Original: Zohre Sharif-Khodai Corrected: Zohreh Sharifkhodaei