Current Drug Metabolism - Volume 25, Issue 2, 2024

Background: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations. Objective: We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity. Results: While seminal in vitro studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition. Conclusions: DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.

Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of daclatasvir or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions, especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt therapy with asunaprevir, daclatasvir and beclabuvir due to the impaired function of important CYPs and transporters.

Preserving host health and homeostasis is largely dependent on the human gut microbiome, a varied and ever-changing population of bacteria living in the gastrointestinal tract. This article aims to explore the multifaceted functions of the gut microbiome and shed light on the evolving field of research investigating the impact of herbal medicines on both the composition and functionality of the gut microbiome. Through a comprehensive overview, we aim to provide insights into the intricate relationship between herbal remedies and the gut microbiome, fostering a better understanding of their potential implications for human health.The gut microbiota is composed of trillions of microorganisms, predominantly bacteria, but also viruses, fungi, and archaea. It functions as a complex ecosystem that interacts with the host in various ways. It aids in nutrient metabolism, modulates the immune system, provides protection against pathogens, and influences host physiology. Moreover, it has been linked to a range of health outcomes, including digestion, metabolic health, and even mental well-being. Recent research has shed light on the potential of herbal medicines to modulate the gut microbiome. Herbal medicines, derived from plants and often used in traditional medicine systems, contain a diverse array of phytochemicals, which can directly or indirectly impact gut microbial composition. These phytochemicals can either act as prebiotics, promoting the growth of beneficial bacteria, or possess antimicrobial properties, targeting harmful pathogens. Several studies have demonstrated the effects of specific herbal medicines on the gut microbiome. For example, extracts from herbs have been shown to enhance the abundance of beneficial bacteria, such as Bifidobacterium and Lactobacillus, while reducing potentially harmful microbes. Moreover, herbal medicines have exhibited promising antimicrobial effects against certain pathogenic bacteria. The modulation of the gut microbiome by herbal medicines has potential therapeutic implications. Research suggests herbal interventions could be harnessed to alleviate gastrointestinal disorders, support immune function, and even impact metabolic health. However, it is important to note that individual responses to herbal treatments can vary due to genetics, diet, and baseline microbiome composition. In conclusion, the gut microbiome is a critical player in maintaining human health, and its modulation by herbal medicines is a burgeoning area of research. Understanding the complex interactions between herbal compounds and gut microbiota will pave the way for innovative approaches to personalized healthcare and the development of herbal-based therapeutics aimed at promoting gut health and overall well-being.

Aims: Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates. Background: Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol. Objectives: The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA. Methods: Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using in silico tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes. Results: Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results. Conclusion: We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required for confirmation of the findings in the vulnerable population.

Background: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. Objectives: The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. Methods: According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. Results: After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. Conclusion: The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

Aims: To evaluate the association between rs4680 polymorphism in the COMT gene and the vasoconstrictive effects of commonly used vasopressors. Background: Dopamine is a medication that is given intravenously to critically ill patients to help increase blood pressure. Catechol O-Methyl Transferase (COMT) breaks down dopamine and other catecholamines. There is a genetic variation in the COMT gene called rs4680 that can affect how well the enzyme works. Studies have shown that people with this genetic variation may have different blood pressure levels. However, no one has looked at how this genetic variation affects the way dopamine works to increase blood pressure. Objectives: To investigate the impact of the rs4680 polymorphism in the COMT gene on the pharmacodynamic response to dopamine. Methods: Critically ill patients administered dopamine were included following the consent of their legally acceptable representatives. Details on their demographic characteristics, diagnosis, drug-related details, changes in the heart rate, blood pressure, and urinary output were obtained. The presence of rs4680 polymorphism in the COMT gene was evaluated using a validated method. Results: One hundred and seventeen patients were recruited, and we observed a prevalence of rs4680 polymorphism in 57.3% of our critically ill patients. Those with mutant genotypes were observed with an increase in the median rate of change in mean arterial pressure (mm Hg/hour) [wild: 8.9 (-22.6 to 49.1); heterozygous mutant: 5.9 (-34.1 to 61.6); and homozygous mutant: 19.5 (-2.5 to 129.2)] and lowered urine output (ml/day) [wild: 1080 (21.4 to 5900); heterozygous mutant: 380 (23.7 to 15800); and homozygous mutant: 316.7 (5.8 to 2308.3)]. Conclusion: V158M (rs4680) polymorphism is widely prevalent in the population and was significantly associated with altered effects as observed clinically. This finding suggests valuable insights into the molecular basis of COMT function and its potential impact on neurotransmitter metabolism and related disorders. Large-scale studies delineating the effect of these polymorphisms on various vasopressors are the need of the hour.

Aim: The aim of this study was to investigate the metabolism of Gelsemium elegans in human, pig, goat and rat liver microsomes and to elucidate the metabolic pathways and cleavage patterns of the Gelsemium alkaloids among different species. Methods: A human, goat, pig and rat liver microsomes were incubated in vitro. After incubating at 37°C for 1 hour and centrifuging, the processed samples were detected by HPLC/Qq-TOFMS was used to detect alcohol extract of Gelsemium elegans and its metabolites. Results: Forty-six natural products were characterized from alcohol extract of Gelsemium elegans and 13 metabolites were identified. These 13 metabolites belong to the gelsemine, koumine, gelsedine, humantenine, yohimbane, and sarpagine classes of alkaloids. The metabolic pathways included oxidation, demethylation and dehydrogenation. After preliminary identification, the metabolites detected in the four species were different. All 13 metabolites were detected in pig and rat microsomes, but no oxidative metabolites of Gelsedine-type alkaloids were detected in goat and human microsomes. Conclusion: In this study, Gelsemium elegans metabolic patterns in different species are clarified and the in vitro metabolism of Gelsemium elegans is investigated. It is of great significance for its clinical development and rational application.

Background: Remimazolam (RMZ) is a novel ultrashort-acting benzodiazepine used for sedation by intravenous administration. The pharmacophore of RMZ includes a carboxyl ester group sensitive to esterase- mediated hydrolysis, which is the primary path of metabolic elimination. However, for the sake of drug safety, a deeper and broader knowledge of the involved metabolic pathways and the evolving metabolites is required. Information is needed on both humans and experimental animals to evaluate the possibility that humans form harmful metabolites not encountered in animal toxicity studies. Objective: The current study aimed at identifying the mechanisms of remimazolam's metabolism and any potential clinically significant metabolites. Methods: Using tissue homogenates from various animals and humans, the liver was identified as the tissue primarily responsible for the elimination of RMZ. CNS7054, the hydrolysis product of remimazolam, was identified as the only clinically relevant metabolite. Using bacterial or eukaryotic over-expression systems, carboxylesterase 1 (CES1) was identified as the iso-enzyme predominantly involved in RMZ metabolism, with no role for carboxylesterase 2. Using a variety of inhibitors of other esterases, the contribution to elimination mediated by esterases other than CES1 was excluded. Results: Besides tissue carboxylesterases, rodents expressed an RMZ esterase in plasma, which was not present in this compartment in other laboratory animals and humans, hampering direct comparisons. Other pathways of metabolic elimination, such as oxidation and glucuronidation, also occurred, but their contribution to overall elimination was minimal. Conclusion: Besides the pharmacologically non-active metabolite CNS7054, no other clinically significant metabolite of remimazolam could be identified.

Objective: This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further. Method: The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes’ activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software. Results: The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3Ц#144;4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing. Conclusion: Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.