Current Drug Metabolism - Volume 24, Issue 8, 2023

Introduction: It is well known that the response to and metabolism of the drugs entering the human body varies widely across individuals. One of the reasons is that such interpersonal differences may be related to gut microbes. On one hand, drugs or xenobiotics entering the human body may affect the composition of the gut microbiome; on the other hand, the gut microbiota may alter the absorption, distribution, metabolism and excretion (abbreviated as ADME) process of drugs or xenobiotics vice versa. However, the majority of studies focused on the interaction of general population cohorts with the gut microbiota, which is incompatible with the real clinic. For example, the gut microbiota is closely associated with the progression and treatment of irritable bowel syndrome, a common functional disorder of the gastrointestinal tract. Under the disease status, the composition of the gut microbiota is altered affecting the pharmacokinetics, efficacy and toxicity of xenobiotics. Concerning irritable bowel syndrome, a few studies reported that the xenobiotics administration process was gut microbial-mediated, while it also affected drug efficacy and toxicity. Thus, the correlation between gut microbiota and xenobiotics administration, especially the drugs administered, should be elucidated. Method: This review paper links differences between the gut microbiome and drug metabolism, which play a significant role in the implications for medical therapy and drug development in irritable bowel syndrome indications. Result: The human intestinal microbiota permeates the ADME process of orally administered drugs and has the potential to further modify the efficacy and toxicity of agents through the mediation of various enzymes, while at the same time, medications could also alter the composition and function of the human intestinal microbiota.

Introduction: The present study has compiled the prevalence of polypharmacy worldwide and assessed the prevalence of polypharmacy in different populations, including community-dwelling individuals, hospitalized patients, and institutionalized patients. Methods: This systematic review was conducted and reported according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A systematic search of electronic databases, including PubMed, Web of Science, and Scielo, was performed in March 2021 without any date and language restrictions. Combinations of the following keywords were used for the search strategy: polypharmacy OR multiple medications OR multiple medicines OR multiple drug AND prevalence. Based on the search and inclusion criteria, two hundred and eight studies (73,076,167 individuals) were selected for inclusion in the systematic review. It was observed that there is a wide variation in the prevalence of polypharmacy between studies. Results: The prevalence of polypharmacy was found to be 30.2%, 61.7%, and 56.9% for community-dwelling individuals, hospitalized patients, and institutionalized patients, respectively. Conclusion: Based on the analyses, this systematic review has demonstrated a wide variation in the prevalence of polypharmacy between studies and countries and a high prevalence of polypharmacy in institutionalized and hospitalized patients.

Background: Chebulinic acid (CA) is an active constituent of Terminalia chebula fruits with therapeutic potential against multiple metabolic diseases, including dementia, benign prostate hyperplasia, and osteoporosis. Objective: The present work intends to explore the preclinical pharmacokinetics, including the absolute bioavailability of CA and its influence on the gene expression of cytochrome P450 enzymes in the liver. Methods: Quantifying CA and probe drugs in vitro samples and preclinical serum samples of male SD rats were performed using LC-MS/MS. The influence of CA on the hepatic CYPs and their gene expression was analyzed in rat liver by quantitative real-time polymerase chain reaction. Results: The plasma protein binding was found to be 84.81 ± 7.70 and 96.34 ± 3.12, blood-to-plasma ratio of 0.62 ± 0.16 and 0.80 ± 0.23 at 1 μM and 10 μM concentrations, respectively. Again, the absolute oral bioavailability of CA at 100 mg/kg was found to be 37.56 ± 7.3%. The in-vivo pharmacokinetic profile of probe drugs revealed CA to have significant inducing effects on CYP1A2, 2C11, 2D2, and 2E1 after 14 days, which correlates to both in-vitro rat microsomal data and gene expression results. Conclusion: Altogether, pharmacokinetic parameters reveal CA to have an affinity to distribute across different extravascular tissues and induce rat liver CYP enzymes.

Background: Nifurtimox is an effective treatment for patients with Chagas disease, but knowledge of its biotransformation and excretion is limited. Objective: This study aimed to better understand the fate of oral nifurtimox in vivo Methods: We investigated the exposure and excretion pathways of [¹⁴C]-labeled nifurtimox and its metabolites in rats. We then quantified the prominent metabolites and nifurtimox in the urine and plasma of patients receiving nifurtimox using LC-HRMS with reference standards and quantified these compounds in rat plasma after a single, high dose of nifurtimox. We also investigated potential drug-drug interactions (DDIs) of these compounds in vitro Results: In rats, orally administered nifurtimox was rapidly absorbed (tmax 0.5 h) and eliminated (t½1.4 h). Metabolism of nifurtimox yielded six predominant metabolites (M-1 to M-6) in urine and plasma, and the dose was excreted equally via the renal and fecal routes with only traces of unchanged nifurtimox detectable due to its instability in excreta. In patients with Chagas disease, only M-6 and M-4 achieved relevant exposure levels, and the total amount of excreted metabolites in urine was higher in fed versus fasted patients, consistent with the higher systemic exposure. For nifurtimox, M-6, and M-4, no potential perpetrator pharmacokinetic DDIs with the main cytochrome P- 450 enzymes and drug transporters were identified in vitro. Conclusion: This contemporary analysis of the complex metabolite profile and associated exposures emerging after oral dosing of nifurtimox in rats and humans, together with the expected low risk for clinically relevant DDIs, expands the understanding of this important anti-trypanosomal drug.

Background: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. Objective: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. Methods: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. Results: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST’s anti-Alzheimer’s disease (AD) and anti-tumor. Conclusion: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).