Current Drug Metabolism - Volume 22, Issue 14, 2021

Abstract: Reactive metabolites (RMs) are products generated from the metabolism of endogenous and exogenous substances. RMs are characterized as electrophilic species chemically reactive to nucleophiles. Those nucleophilic species may be nitrogen-containing bio-molecules, including macro-biomolecules, such as protein and DNA, and small biomolecules, i.e., amino acids (AAs) and biogenic amines (BAs). AAs and BAs are essential endogenous nitrogen-containing compounds required for normal development, metabolism, and physiological functions in organisms, through participating in the intracellular replication, transcription, translation, division and proliferation, DNA and protein synthesis, regulation of apoptosis, and intercellular communication activities. These biological amines containing an active lone pair of electrons on the electronegative nitrogen atom would be the proper N-nucleophiles to be attacked by the abovementioned RMs. This review covers an overview of adductions of AAs and BAs with varieties of RMs. These RMs are formed from metabolic activation of furans, naphthalene, benzene, and products of lipid peroxidation. This article is designed to provide readers with a better understanding of biochemical mechanisms of toxic action.

Abstract: Glioblastoma multiforme (GBM) is a typical category of the most common and aggressive brain tumors, with a high incidence in older adults, particularly in males. Although the etiology of GBM has not been fully elucidated, yet it is characterized by highly proliferative activity in the glial cells. Its complete resection is impossible, and radiotherapy is not always efficient for complete relief. Thus, GBM remains a therapeutic challenge in neurooncology as there is no treatment that provides significant improvement in the survival rate of patients. In this regard, the identification of newer drug therapy for the treatment of GBM is gaining popularity. However, identifying new targets and developing new leads for screening suitable drug candidates require the investment of resources like time, money, and efforts. It has been observed in many research studies that the use of polyunsaturated fatty acids (PUFAs) as therapeutic moieties for cancer treatment has yielded significant interest owing to their cost-effective availability, limited side effects, and insensitivity towards drug resistance. Nevertheless, the implications of nanostructured therapeutic systems in delivering the PUFAs can provide significant improvement in their biopharmaceutical performance and antitumor activity over the existing alkylating agents used as chemotherapeutic drugs in GBM. Currently, various studies have shown that PUFAs, especially γ-linolenic acid (GLA), have selective tumoricidal action and the ability to reduce antioxidant contents of the glioma tumor cells. In this regard, the present review endeavors to provide an insight into the applications of nanomedicinal drug carriers used for delivering the PUFAs for the effective treatment of GBM and associated diseases.

Background: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines. Objective: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions. Method: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance. Result: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC50: 3.8 and 5.4 μg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 μg/mL, respectively). Conclusion: Our studies suggested that the medicinal plants’ extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo.

Background: MIDD0301 is an oral asthma drug candidate that binds GABAA receptors on airway smooth muscle and immune cells. Objective: The objective of this study is to identify and quantify MIDD0301 metabolites in vitro and in vivo and determine the pharmacokinetics of oral, IP, and IV administered MIDD0301. Methods: In vitro conversion of MIDD0301 was performed using liver and kidney microsomes/S9 fractions followed by quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A LC-MS/MS method was developed using synthesized standards to quantify MIDD0301 and its metabolites in urine and feces. Blood, lung, and brain were harvested from animals that received MIDD0301 by oral, IP, and IV administration, followed by LCMS/ MS quantification. Imaging mass spectrometry was used to demonstrate the presence of MIDD0301 in the lung after oral administration. Results: MIDD0301 is stable in the presence of liver and kidney microsomes and S9 fractions for at least two hours. MIDD0301 undergoes conversion to the corresponding glucuronide and glucoside in the presence of conjugating cofactors. For IP and IV administration, unconjugated MIDD0301 together with significant amounts of MIDD0301 glucoside and MIDD0301 taurine were found in urine and feces. Less conjugation was observed following oral administration, with MIDD0301 glucuronide being the main metabolite. Pharmacokinetic quantification of MIDD0301 in blood, lung, and brain showed very low levels of MIDD0301 in the brain after oral, IV, or IP administration. The drug half-life in these tissues ranged between 4-6 hours for IP and oral and 1-2 hours for IV administration. Imaging mass spectrometry demonstrated that orally administered MIDD0301 distributes uniformly in the lung parenchyma. Conclusion: MIDD0301 undergoes no phase I and moderate phase II metabolism.

Background: Significant changes in the pathophysiology of older critically ill patients may affect the pharmacokinetics and pharmacodynamics of teicoplanin. This study aimed to determine the optimal teicoplanin blood level in this patient population. Methods: 128 older critically ill and 86 older non-critically ill patients were involved and analyzed. Results: The target thresholds of teicoplanin blood concentrations in older critically ill patients and non-critically ill patients should be 31.4mg/L and 15.3mg/L, respectively. The dose of teicoplanin in older critically ill patients should be greater than 800 mg to achieve the target blood level. Conclusion: An individualized dosing approach of teicoplanin based on therapeutic drug monitoring is necessary for older critically ill patients.

Objective: The aim of the study was to investigate a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of rivaroxaban and evaluate the correlation between plasma concentration and anti-Xa activity in patients using oral rivaroxaban. Methods: In this study, the plasma concentration of rivaroxaban and anti-Xa factor activities was determined in 125 patients, and the relationship between the two variables was analysed by SPSS 21.0 software. Results: The results showed that the plasma concentrations of oral rivaroxaban patients were significantly correlated with the activity of the anti-Xa factor (Spearman’s r = 0.990, P < 0.05). Conclusion: The plasma concentrations of rivaroxaban are a potentially useful monitoring indicator to assess the patient’s bleeding risk if testing for plasma anti-Xa activity is not available.

Background: Increased generation of reactive oxygen and nitrogen species in chronic kidney disease (CKD) patients leads to increased oxidative stress. The antioxidant capacity of folic acid has been shown to scavenge radicals efficiently. Objective: The current study was carried out to examine the effects of folic acid treatment on biochemical and oxidative stress biomarkers in patients in different stages of CKD. Methods: This was a randomized, non-blinded, clinical trial that assessed the effects of 3 months of treatment with 5 mg of folic acid daily or no treatment in 113 outpatients within CKD stages 3a and 3b. At the end of the intervention, we analyzed the data of 66 patients treated with folic acid and 47 in the control group. Serum homocysteine levels and biochemical and oxidative/nitrosative stress biomarkers were analyzed in all patients. Results: In most patients, folic acid treatment normalized homocysteine levels and increased antioxidant enzyme activity (paraoxonase 1) and decreased sulfhydryl (SH) groups. In addition, oxidative biomarkers (products of nitric oxide and lipid hydroperoxide) were significantly lower post-treatment compared to baseline in the active intervention group. In the no active intervention group, no statistically significant effects were found on the oxidative and biochemical biomarkers. Conclusion: Folic acid treatment in stages 3a-4 CKD patients effectively ameliorated their hyperhomocysteinemia and increased the activity of antioxidant enzymes, as well as decreased the levels of pro-oxidant biomarkers in stage G3a and G3b CKD patients. Folic acid treatment attenuated oxidative/nitrosative stress and may be considered as a possible strategy to improve redox status and diminish the damages associated with oxidative/nitrosative stress in CKD patients. Further studies are needed to confirm these findings. Clinical Trials Registration No.: This study is registered in the Brazilian Record of Clinical Trials (ReBEC), under reference RBR-2bfthr.