Curr. Drug Metab. [JOURNAL]
Sun
200 papers
Prediction of Pharmacokinetics of Valeric Acid: Alternative Tool to Minimize Animal Studies.
Kumari B, Singh DK, Singh RB … +1 more , Singh GK
Curr Drug Metab · 2025 · PMID 40108920 · Publisher ↗
BACKGROUND: The use of computer-aided toxicity and Pharmacokinetic (PK) prediction studies are of significant interest to pharmaceutical industries as a complementary approach to traditional experimental methods in predi...
BACKGROUND: The use of computer-aided toxicity and Pharmacokinetic (PK) prediction studies are of significant interest to pharmaceutical industries as a complementary approach to traditional experimental methods in predicting potential drug candidates. METHODS: In the present study, pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of valeric acid were examined using SwissADME and ADMETlab web tools. RESULTS: The drug-likeness prediction results revealed that valeric acid adheres to the Lipinski rule, Pfizer rule, and GlaxoSmithKline (GSK) rule. From a pharmacokinetic perspective, valeric acid is anticipated to have the best absorption profile including cell permeability and bioavailability. Plasma Protein Binding (PPB) and Blood-Brain Barrier (BBB) permeability may have a positive effect on Central Nervous System modulating (CNS). There is a minimal chance of it being a substrate for cytochrome P2D6 (CYP). Except for a "very slight risk" for eye corrosion and eye irritation, none of the well-known toxicities in valeric acid were anticipated, which was compatible with wet-lab data. The molecule possesses no environmental hazard as analyzed with common indicators such as bio-concentration factor and LC for fathead minnow and daphnia magna. The toxicity parameters identified valeric acid as nontoxic to androgen receptors, antioxidant response element, mitochondrial membrane receptor, heat shock element, and tumor suppressor protein (p53), except Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) was found to be medium toxicity. However, no toxicophores were found out of seven parameters. CONCLUSION: Overall, the ADMETLab evaluated that valeric acid has favorable pharmacokinetic and drug-likeness profiles, making it a promising drug candidate for new drug development.
Effect of Capsule (WZC) on the Pharmacokinetics of Tacrolimus in Renal Transplantation Recipients.
Zhang W, Wang R, Li L … +7 more , Chen J, Zhai J, Wang W, Liu S, Liu H, Wei H, Han S
Curr Drug Metab · 2025 · PMID 40108919 · Publisher ↗
BACKGROUND: Previous studies have shown that WZC can increase tacrolimus blood concentration when co-administered. However, limited knowledge exists regarding the pharmacokinetics of both tacrolimus and the bioactive lig...
BACKGROUND: Previous studies have shown that WZC can increase tacrolimus blood concentration when co-administered. However, limited knowledge exists regarding the pharmacokinetics of both tacrolimus and the bioactive lignans in WZC when administered simultaneously in renal transplantation patients. AIMS: This study aimed to investigate the pharmacokinetics of tacrolimus and multiple bioactive lignans in Wuzhi capsule (WZC) when co-administered with 5 bioactive components in renal transplantation recipients. OBJECTIVES: The objective of this study was to develop a method for simultaneous quantification of tacrolimus and multiple bioactive lignans in WZC using liquid-liquid extraction followed by LC-MS/MS analysis. METHODS: A liquid-liquid extraction method combined with LC-MS/MS analysis was developed for simultaneous quantification of tacrolimus and multiple bioactive lignans in WZC. Human whole blood samples were analyzed, and the accuracy and precision of the method were evaluated. RESULTS: The developed method showed good linearity and accuracy for the quantification of tacrolimus and bioactive lignans in WZC. Pharmacokinetic analysis revealed significant effects of WZC co-administration on both V/F and CL/F in renal transplantation patients. CONCLUSION: This study demonstrated that simultaneous administration of WZC had notable effects on the pharmacokinetics of tacrolimus and bioactive lignans in renal transplantation patients. The developed method proved to be reliable and sensitive for determining the whole blood concentrations of tacrolimus and WZC, making it suitable for pharmacokinetic studies in transplant patients.
Comparative in Vitro Metabolic Profile Study of Five Cathinone Derivatives.
Li Z, Xiang S, Zheng T … +2 more , Wu G, Wu L
Curr Drug Metab · 2025 Mar · PMID 40103476 · Publisher ↗
BACKGROUND: Cathinone derivatives as new psychoactive substances have attracted worldwide attention in recent years. They have strong excitatory effects on the human central nervous system, which is extremely abusive and...
BACKGROUND: Cathinone derivatives as new psychoactive substances have attracted worldwide attention in recent years. They have strong excitatory effects on the human central nervous system, which is extremely abusive and harmful. As they are easy to be structurally modified, and rapidly metabolized and excreted after taken, clarifying their metabolic profile is of significant importance to provide useful information for their identification or forensic purposes. OBJECTIVE: In this paper, a comparative in vitro metabolic profile study of five cathinone derivatives (4/3/2- methylmethcathinone and 4/3-methoxymethcathinone) was performed, including their metabolic stability in the simulated gastrointestinal tract, mass spectrometry fragmentation behavior, possible metabolic pathways and metabolites in human liver microsomal incubation system, and revealing the key metabolic enzyme isoforms involving in their biotransformation. METHODS: In vitro incubation was performed in simulated gastric/intestinal fluid and human liver microsomes, fragmentation behavior study and metabolite identification were investigated by LC-Q-TOF/MS, and metabolic stability study, along with metabolic enzyme screening were analyzed using LC-MS/MS. RESULTS: Almost all the cathinone derivatives tested were stable in the simulated gastric/intestinal fluid; characteristic fragmentation pathway and diagnostic fragment ions of the cathinone derivatives were analyzed; the key metabolic pathways of 4/3-methylmethcathinone and 4/3-methoxymethcathinone revealed were hydroxylation and demethylation, which were catalyzed by CYP2D6. The methyl-substituted position would significantly affect the metabolic pathway of the methylmethcathinone. CONCLUSION: This study revealed the mass spectral fragmentation pattern and the in vitro metabolic behavior of the selected cathinone derivatives, providing meaningful information and scientific evidence in predicting their metabolic potential in vivo, and also promoting their analysis, detection, and clinical use.
Transformative CRISPR-Cas9 Technologies: A Review of Molecular Mechanisms, Precision Editing Techniques, and Clinical Progress in Sickle Cell Disease.
Komal, Kaur P, Arora N … +2 more , Sawale JA, Singh A
Curr Drug Metab · 2025 Mar · PMID 40045853 · Publisher ↗
Sickle cell disease (SCD) is a hereditary blood disorder resulting from the production of distorted hemoglobin molecules that cause red blood cells to adopt a sickle or crescent-like shape. This disease affects millions...
Sickle cell disease (SCD) is a hereditary blood disorder resulting from the production of distorted hemoglobin molecules that cause red blood cells to adopt a sickle or crescent-like shape. This disease affects millions of people, particularly those of African, Mediterranean, Middle Eastern, or South Asian descent. In recent years, however, advancements in the CRISPR-Cas9 gene-editing systems have surged. CRISPR stands for clustered regularly interspaced short palindromic repeats, referring to a specific organization of short, partially repeated DNA sequences in prokaryotic genomes. The CRISPR-Cas9 technique is based on the type II CRISPR system of bacteria and involves the Cas9 nuclease, which is targeted to a particular genome section with the help of single-guide RNA. Initially used for random mutations and small sequence alterations, genome editing methods have advanced to achieve large-scale DNA segment manipulation. The BE and PE-- type CRISPR-Cas9 genome editing variants provide new therapeutic options for genetic disorders, improving patients' prognosis. Curative gene editing using CRISPR-Cas9 technology to correct HBB gene mutations that cause SCD represents a revolutionary therapeutic development. These advances bring new hope to patients with previously untreatable diseases, potentially offering a future where genetic disorders can be addressed at their roots. A major objective of CRISPR technology is to enhance its precision and speed, both critical for effective gene editing. This review focuses on molecular mechanisms of CRISPR-Cas9 technology, CRISPR-- Cas9-based approaches for HBB gene modification, clinical trials, patients with sickle cell disease, and advances in CRISPR technology for sickle cell disease.
Corrigendum To: Establishment of a High Content Image Platform to Measure NF-κB Nuclear Translocation in LPS-induced RAW264.7 Macrophages for Screening Anti-inflammatory Drug Candidates.
Zhang YY, Yao YD, Cheng QQ … +2 more , Huang YF, Zhou H
Curr Drug Metab · 2025 · PMID 39957293 · Publisher ↗
In the article titled "Establishment of a High Content Image Platform to Measure NF-κB Nuclear Translocation in LPSinduced RAW264.7 Macrophages for Screening Anti-inflammatory Drug Candidates" published in Current Drug M...
In the article titled "Establishment of a High Content Image Platform to Measure NF-κB Nuclear Translocation in LPSinduced RAW264.7 Macrophages for Screening Anti-inflammatory Drug Candidates" published in Current Drug Metabolism, Volume 23, No. 5, 2022, pp. 394-414 [1], the authors have identified error in Fig. (8C). They request correction to this figure to ensure accuracy in the representation of their findings. We regret the error and apologize to readers. The original article can be found online at: https://www.eurekaselect.com/article/122464.
In vitro and In vivo Drug Metabolism Analysis of BPI-460372 - A Covalent TEAD1/3/4 Inhibitor.
Liu X, Zhong D, Tang CZ … +3 more , Xu X, Lan H, Diao X
Curr Drug Metab · 2025 Feb · PMID 39950481 · Full text
BACKGROUND: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment o...
BACKGROUND: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations. OBJECTIVE: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372. METHODS: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS). RESULTS: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree. CONCLUSION: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.
Potential Alteration of Rifampicin's Bioavailability by Phyllanthus niruri Supplementation in Tuberculosis Therapy.
Ardana M, Laksitorini MD, Lukitaningsih E … +1 more , Nugroho AE
Curr Drug Metab · 2025 Feb · PMID 39936409 · Publisher ↗
Rifampicin is essential for treating TB. The high incidence of resistance to this drug requires efforts to increase the effectiveness of TB therapy. Immunomodulator supplementation is one effort to overcome this problem....
Rifampicin is essential for treating TB. The high incidence of resistance to this drug requires efforts to increase the effectiveness of TB therapy. Immunomodulator supplementation is one effort to overcome this problem. Phyllanthus niruri has an immunomodulating effect, which has been proven to influence the clinical improvement of the immunological profile. However, the effect of this plant on rifampicin's bioavailability should be reviewed to determine potential changes that may affect its antibacterial performance. Several stud-ies have shown an increase in the bioavailability of rifampicin when administered with extracts and active isolates of Carum carvi, Cuminum cyminum, Piper nigrum, and Moringa oleifera through inhibition of the P-gp efflux function in the absorption phase. On the other hand, the decrease occurred in coadministration with Garcinia cola, which activated PXR action and subsequently changed P-gp regulation. Administration of Al-lium sativum and Zingiber officinale extracts did not show significant alteration in bioavailability due to the stimulation of several mechanisms with opposite outputs by each secondary metabolite. In the case of P. niruri supplementation, the potential for a rise in bioavailability could occur due to synergistic effects inhibiting the performance of P-gp, AADAC, and OATP1B. However, the stimulation of PXR and PPARα may reduce or eliminate these effects. Finally, considering that there are so many specific secondary metabolites in P. niruri whose effects on the performance of these functional proteins have not been exposed, in vivo studies are needed to confirm the interactions within complex biological systems.
A Review on Drug-Metabolizing Enzymes, Transporters, and Gut Microbiota on Pharmacokinetics in High-Altitude Environment.
Qiu F, Sun Y, Li W … +1 more , Wang R
Curr Drug Metab · 2025 Feb · PMID 39931992 · Publisher ↗
The most significant feature of the high-altitude environment is hypoxia, which affects the activity and expression of drug-metabolizing enzymes and transporters, leading to changes in pharmacokinetic parameters. Notably...
The most significant feature of the high-altitude environment is hypoxia, which affects the activity and expression of drug-metabolizing enzymes and transporters, leading to changes in pharmacokinetic parameters. Notably, gut microbiota is a hidden organ in the body. High-altitude hypoxia will change the composition and quantity of gut microbiota, affect drug metabolism, and change the bioavailability of drugs. This will provide a new perspective on changes in pharmacokinetics at high-altitude. Most studies have revealed that for drugs with low bioavailability and high clearance, the dosage may be increased accordingly. Conversely, the dosage may be reduced to achieve individualized medication. Therefore, this article reviews the changes and mechanisms of drug-metabolizing enzymes, transporters, and gut microbiota in a high-altitude environment and explains the impact of their changes on pharmacokinetics, aiming to provide theories and bases for the adjustment of drug dosage and the rational use of drugs in the clinic under high-altitude environment.
Umbelliferone Enhances Immune Function in Cyclophosphamide-Induced Immunosuppressed Mice Histidine and Purine Metabolism Regulation.
Li M, Wang J, Huo B … +7 more , Wan Q, Xing L, Wang Y, Pei H, Wang L, Xia Y, Cui H
Curr Drug Metab · 2024 · PMID 39931991 · Publisher ↗
BACKGROUND: Chemotherapy-induced immunosuppression significantly impacts patient's quality of life. Umbelliferone (UMB) is known for its anti-inflammatory, antioxidant, and anti-apoptotic properties, but its effects on c...
BACKGROUND: Chemotherapy-induced immunosuppression significantly impacts patient's quality of life. Umbelliferone (UMB) is known for its anti-inflammatory, antioxidant, and anti-apoptotic properties, but its effects on cyclophosphamide (CTX)-induced immunosuppression need further study. METHODS: We established a CTX-induced immunosuppressed mouse model and administered varying doses of UMB. Immune function was assessed by evaluating white blood cells, lymphocytes, thymus and spleen indices, and CD4/CD8 T cell ratios. Serum levels of IL-2, IFN-γ, IgA, IgM, and IgG, along with macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation, were measured. Untargeted metabolomics was used to identify key pathways regulated by UMB, and RT-qPCR and Western blotting were performed to analyze the expression of related enzymes and metabolites. RESULTS: UMB intervention increased white blood cells, lymphocytes, thymus and spleen indices, and CD4+/CD8+ T cell ratios in CTX-immunosuppressed mice. It reversed reduced levels of serum IL-2, IFN-γ, IgA, IgM, and IgG and improved macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation. Key pathways identified by metabolomics included histidine and purine metabolism. UMB improved levels of histamine, L-glutamate, L-aspartate, xanthine, dAMP, deoxyinosine, xanthosine, and cGMP and upregulated HDC, ASPA, and PNP while downregulating XDH, PDE5, ROS, and MDA in spleen tissue. UMB enhanced SOD activity and GSH levels and reduced apoptosis, as indicated by lower TUNEL-positive expression. CONCLUSION: UMB enhanced immune function in CTX-immunosuppressed mice through the regulation of histidine and purine metabolism, exhibiting antioxidant and anti-apoptotic effects. These findings highlight the potential of UMB in mitigating immunosuppression.
Pharmacokinetic Interactions of Paxlovid Involving CYP3A Enzymes and P-gp Transporter: An Overview of Clinical Data.
Maideen NMP, Kandasamy K, Balasubramanian R
Curr Drug Metab · 2024 · PMID 39917926 · Publisher ↗
BACKGROUND: The US FDA has approved paxlovid, a combination of nirmatrelvir and ritonavir, as the first oral treatment for the management of mild-to-moderate COVID-19 patients. OBJECTIVE: The purpose of this review artic...
BACKGROUND: The US FDA has approved paxlovid, a combination of nirmatrelvir and ritonavir, as the first oral treatment for the management of mild-to-moderate COVID-19 patients. OBJECTIVE: The purpose of this review article is to explore the clinical data that is currently available regarding the drug-drug interactions (DDIs) of paxlovid with various medications. METHODS: Keywords, such as drug interactions, paxlovid, ritonavir, nirmatrelvir, pharmacokinetic interactions, CYP3A, and P-glycoprotein, were used to search online databases, including LitCOVID, Scopus, Embase, EBSCO host, Google Scholar, ScienceDirect, Cochrane Library, and reference lists. RESULTS: Paxlovid interacted with a variety of medications due to strong inhibition of CYP3A4 and P-gp transporter protein by ritonavir and the dual function of nirmatrelvir as a substrate and inhibitor of CYP3A enzymes and P-gp transporter protein. Numerous case reports and other studies determined that the risk of toxicities of several drugs, including anticoagulants (warfarin, rivaroxaban), calcium channel blockers (nifedipine, manidipine, verapamil), statins (atorvastatin), immunosuppressants (tacrolimus), antiarrhythmics (amiodarone), antipsychotics (clozapine, quetiapine), and ranolazine have been enhanced by the concomitant administration of paxlovid. CONCLUSION: Adverse effects of paxlovid from DDIs can range from less-than-ideal therapeutic responses to potentially fatal toxicities. Effective management requires close observation, adjustments to dosage, and assessment of substitute treatments. Collaboration between pharmacists and other medical professionals is necessary to guarantee effective and safe treatment outcomes of paxlovid therapy.
Effects of Shenmai Injection on the Pharmacokinetics of Dasatinib: An In-Depth Analysis Utilizing UPLC-MS/MS Technique.
Ma W, Li L, Li Z … +5 more , Guo J, Zhu Y, Ge L, Wang R, Lv L
Curr Drug Metab · 2024 · PMID 39901553 · Publisher ↗
BACKGROUND: Dasatinib has been widely used in the treatment of a variety of cancers, such as lung cancer and acute myeloid leukemia. Shenmai injection is a traditional Chinese medicine injection that is often used in ant...
BACKGROUND: Dasatinib has been widely used in the treatment of a variety of cancers, such as lung cancer and acute myeloid leukemia. Shenmai injection is a traditional Chinese medicine injection that is often used in antitumor adjuvant therapy. In recent years, dasatinib combined with Shenmai injection has been increasingly used to treat tumors clinically. However, the potential risks and benefits of co-administering Shenmai injection and dasatinib are unclear. OBJECTIVE: The study aimed to investigate the potential influence of Shenmai injection on dasatinib pharmacokinetics. METHODS: Twelve rats were selected and randomly divided into two groups: dasatinib alone and a combination of dasatinib and Shenmai injection. To measure the concentration of dasatinib in rat plasma, blood samples were obtained from the orbital vein. Using ultra-performance liquid chromatography-tandem mass spectrometry, the concentration of dasatinib was determined to obtain pharmacokinetic parameters. RESULTS: Compared to the dasatinib alone administration, the maximum concentration of the dasatinib plus Shenmai injection administration was decreased (355.9 ± 194.9 vs. 199.2 ± 73.8 ng·mL) (P < 0.05). Moreover, the area under the moment curve (3867.0 ± 2141.9 vs. 6355.3 ± 3311.6 ng·mL·h) and mean residence time (3.7 ± 1.2 vs. 6.5 ± 3.1 h) showed a statistically significant increase (P < 0.05). CONCLUSION: The study revealed that Shenmai injection might have the capacity to slow down the absorption rate of dasatinib and could extend the retention period of dasatinib in the body, resulting in stabilized blood drug concentrations and a reduction in adverse drug reactions.
Hallmarks of Quercetin Benefits as a Functional Supplementary in the Management of Diabetes Mellitus-Related Maladies: From Basic to Clinical Applications.
Farhadi F, Sharififar F, Jafari M … +3 more , Rahimi VB, Askari N, Askari VR
Curr Drug Metab · 2024 · PMID 39878112 · Publisher ↗
Quercetin (QE), a particular flavonoid, is well known for its medicinal effects, including anti-oxidant, hypoglycemic, and anti-inflammatory effects. In this review, the findings of QE effects on diabetes STZinduced, all...
Quercetin (QE), a particular flavonoid, is well known for its medicinal effects, including anti-oxidant, hypoglycemic, and anti-inflammatory effects. In this review, the findings of QE effects on diabetes STZinduced, alloxan-induced, and its complications have been summarized with a particular focus on in vitro, in vivo, and clinical trials. Consequently, QE mediates several mechanisms, including ameliorating tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β, IL-8, and IL-10 expression, increasing insulin glucose uptake to inhibit insulin resistance. Moreover, QE stimulates insulin secretion and attenuates insulin resistance through various pathways, namely transient KATP channel, motivating peroxisome proliferator-activated receptor expression, increasing glucose transporter-4, and decreasing inducible nitric oxide synthase in skeletal muscle. QE has protective effects on the complications caused by diabetes, such as polycystic ovary syndrome, high-fat diet-induced obesity, diabetic-induced hepatic damage, vascular inflammation, nephropathy, and neuropathy.
Exploring Drug-Drug Interactions between Losartan and Carbamazepine: A Pharmacokinetic and Pharmacodynamic Study.
Sundargowda SA, Kadiri SK
Curr Drug Metab · 2024 · PMID 39851122 · Publisher ↗
BACKGROUND: Hypertension, which affects 1.28 billion people globally aged 30 to 79, is characterized by continuously high blood pressure (140/90 or more) and raises the risk of premature death. Losartan, an angiotensin r...
BACKGROUND: Hypertension, which affects 1.28 billion people globally aged 30 to 79, is characterized by continuously high blood pressure (140/90 or more) and raises the risk of premature death. Losartan, an angiotensin receptor blocker (ARB), is suggested for patients under the age of 55 who cannot take ACE inhibitors as a first treatment option. Epilepsy, a chronic neurological illness marked by repeated seizures, affects more than 50 million individuals worldwide and is the third most common chronic brain disorder. Both hypertension and epilepsy are frequent chronic illnesses, with increased blood pressure greatly raising the risk of epilepsy due to its relationship with cerebrovascular disease, doubling the risk when compared to people with normal blood pressure. OBJECTIVE: The effect on pharmacokinetics and pharmacodynamics of losartan on concomitant administration with carbamazepine was investigated. MATERIALS AND METHODS: Wistar rats of either sex, with a minimum of six animals per group, were used in the investigation. The rats were treated with Losartan and Losartan-Carbamazepine for 30 days. Blood samples were taken via retro-orbital plexus at 0, 1, 2, 4, 6, and 12 hours after treatment concluded, and they were subjected to high-performance liquid chromatography for plasma analysis to calculate AUC, t1/2, and Clearance. A pharmacodynamic evaluation was done by inducing hypertension in rats using a 10% fructose solution and the effect of pretreated Losartan and Losartan-Carbamazepine on blood pressure was determined. RESULTS: In the Losartan and Carbamazepine treated group, there was a reduction in the AUC and t1/2 and a reported increase in the clearance value compared to Losartan alone treated rats. In fructose-induced hypertension model to evaluate the effect of losartan and carbamazepine on BP showed an increase in mean arterial pressure, plasma glucose, and a reduction in triglycerides level was noted in comparison to Losartan alone treated rats indicating therapeutic failure of Losartan. CONCLUSION: Based on these studies, it is concluded that CBZ has reduced the effectiveness of losartan and therefore, co-administration of these drugs should be avoided.
Characterization of Five Natural Anthraquinone Compounds as Potent Inhibitors against CYP1B1: Implications for Cancer Treatment.
Chen Z, Xu Z, Chen X … +5 more , Guan X, Du J, Zhang J, Wang C, Wu J
Curr Drug Metab · 2024 · PMID 39838665 · Publisher ↗
BACKGROUND: Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme that is overexpressed in many tumors and is associated with tumor development and acquired resistance. Few studies have reported that anthraquinone...
BACKGROUND: Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme that is overexpressed in many tumors and is associated with tumor development and acquired resistance. Few studies have reported that anthraquinone compounds have inhibitory activity against the CYP1B1 enzyme. Cassiae semen (Leguminosae) is a well-known traditional Chinese medicine containing more than 70 compounds. The crude extracts and pure compounds of have been widely used in preclinical and clinical practice for their beneficial effects, such as neuroprotective, hepatoprotective, antimicrobial, antioxidant, and hypotensive effects. Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein are important active natural anthraquinones in Cassiae semen. OBJECTIVE: Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein have a wide range of pharmacological activities and have been found to have good anti-tumor and antioxidant effects. However, the underlying mechanisms of these pharmacological activities remain poorly understood. This study aimed to investigate the inhibitory effects of five natural anthraquinones on the activity of CYP1B1 and to analyze the structure- activity relationship of these compounds. MATERIALS AND METHODS: In this study, 7-ethoxyresorufin O-deethylation (EROD) was used as the fluorescent substrate of CYP1B1 to investigate the inhibition effect, and molecular docking was performed to further determine the structural-activity relationship of the compound molecules. RESULTS: We found that aloe-emodin and chrysophanol had strong inhibitory effects on CYP1B1 with IC values of 0.28 and 0.34μM, respectively, while obtusifolin and aurantio-obtusin had IC values of 0.77μM and 9.11μM, respectively. The structural activity analysis showed that the inhibition strength was related to the position of the hydroxyl group substitution and the number of methoxy group substitutions. Rhein containing one carboxyl group showed the weakest inhibition of 23.72μM. The inhibition kinetics showed that all five compounds belonged to the non-competitive inhibition model. The inhibition kinetics revealed that all five compounds exhibited the non-competitive inhibition model. CONCLUSION: The present study provided a comprehensive analysis of the inhibitory effects of five natural anthraquinones, namely aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin and rhein, on CYP1B1 activity, and elucidated the structure-activity relationship. Molecular docking simulations further revealed the specific amino acid residues within the active site of CYP1B1, where these compounds exerted their actions. These findings offer novel insights into investigating the potential antitumor properties of natural anthraquinones.
Tacrolimus, Cytochrome P450, Interactions with Food Variables in Organ Transplant Recipients; A Current and Comprehensive Review.
Tolou-Ghamari Z
Curr Drug Metab · 2025 · PMID 39757635 · Publisher ↗
The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many featu...
The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many features associated with food parameters like phytochemicals, juices, and fruits. This review article summarizes the findings of previous studies to help predict the efficacy or side effects of tacrolimus in the presence of food variables. From the commencement of databases associated with the topic of interest to 26 October 2024, all relevant articles were searched through PubMed, Scopus, and Web of Science. The suggested therapeutic range for tacrolimus trough concentration (C ) was reported as 5-15 ng/ml blood. Tacrolimus interaction with food variables could significantly change C after organ transplantation. For example, grapefruit juice could increase tacrolimus C due to CYP enzyme inhibition. Toxicity such as nephrotoxicity could result from turmeric and other herbal or food products. By inhibiting tacrolimus-metabolizing enzymes and transporters, a high intake of vegetables could increase the risk of adverse effects. Secondary metabolites of vegetables could lead to toxicity in patients with tacrolimus. Furthermore, grapefruit juice, citrus fruits, turmeric, and pomegranate juice could change clinical pharmacokinetics parameters such as T, C, AUC, and C of tacrolimus after organ transplantation. Bioavailability of tacrolimus might be decreased by induction of the CYP450 system and P-gp efflux pump due to cranberry, rooibos tea, and boldo. Increased inhibitory effect on CYP450 system and/or P-gp efflux pump by grapefruit juice, schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger could increase bioavailability of tacrolimus. A vigilant immunosuppressive strategy accompanied by scheduled therapeutic drug monitoring is recommended before and after transplant surgery.
Metabolic and Pharmacokinetic Perspectives on Hepatotoxic Agents in Experimental Cirrhosis.
Mehra A, Mittal R, Mittal A … +5 more , Sangwan R, Roy T, Mittal A, Raj N, Kohli R
Curr Drug Metab · 2025 · PMID 41714922 · Publisher ↗
Cirrhosis is a very serious, gradual liver disease characterized by the overproduction of collagen and scarring, which together may result in liver failure or hepatocellular cancer. It typically develops based on fibrosi...
Cirrhosis is a very serious, gradual liver disease characterized by the overproduction of collagen and scarring, which together may result in liver failure or hepatocellular cancer. It typically develops based on fibrosis, which may be reversible when diagnosed in its initial stages. Viral hepatitis, alcohol, non-alcoholic fatty liver disease, and drug-induced hepatotoxicity are some of the etiologies of the disease. It is worth noting that about half of the cases of hepatic damage in patients are known to be caused by drug-induced liver injury. The existence of the pathophysiological complexity and therapeutic reactions of cirrhosis requires experimental models that are reliable. This review gives insight into the different , and operative animal models employed to cause hepatic injury by application of chemicals, drugs, dietary, and bile duct ligation particulars. The focus is on the mechanistic understanding of the actions of hepatotoxic substances, their involvement in oxidative stress, mitochondrial pathology, and the inflammatory process. Each model is critically discussed in terms of its advantages, limitations, and translational relevance.Additionally, this work highlights emerging alternatives, such as organ-on-a-chip systems, 3D co-cultures, and hepatic bioengineered tissues, as solutions that aim to reduce animal use and increase physiological relevance. The review also discusses biomarkers, histopathological endpoints, and important molecular players in hepatic fibrosis and cirrhosis. The review also examines data from preclinical studies of hepatoprotective substances and modulators of fibrosis, as it facilitates the integration of data from various experimental platforms. The next steps involve personalized pathology based on decellularized liver scaffolding and patient cells, aiming to better determine clinical outcomes and treatment responses.
Recent Insights into Nano-mediated siRNA Drug Delivery.
Krishnaswami V, Janakiraman K, Sethuraman V … +3 more , Raja J, Muruganantham S, Chelladurai S
Curr Drug Metab · 2025 · PMID 39716803 · Publisher ↗
Gene silencing is the characteristic that inhibits gene expression afforded by siRNA interference. The efficacy of the delivery system in terms of precision, efficacy, and stability can be enhanced by genebased drug deli...
Gene silencing is the characteristic that inhibits gene expression afforded by siRNA interference. The efficacy of the delivery system in terms of precision, efficacy, and stability can be enhanced by genebased drug delivery options. The delivery challenges and their associated side effects create a challenge for the delivery of gene-based drug delivery carriers. Nano-based delivery systems were reported to improve the efficacy of therapy. The absence of an efficient delivery mechanism that shields siRNA from nuclease degradation delivers it to cancer cells, and releases it into the cytoplasm of specific cancer cells without causing side effects is currently the greatest obstacle to the practical implementation of siRNA therapy. This article focuses on general aspects of siRNA and various siRNA nanocarrier-based formulations. In the near future, we will move towards the siRNA-based drug delivery approach.
Pharmacokinetic Interaction between Imatinib and Tacrolimus in Rats.
Fan N, Guo T, Du L … +2 more , Liu M, Chen X
Curr Drug Metab · 2025 · PMID 39716802 · Publisher ↗
OBJECTIVE: Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the...
OBJECTIVE: Tacrolimus, a calcineurin inhibitor (CNI), is the first-line treatment for chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Imatinib and tacrolimus are both substrates of the hepatic enzymes CYP3A4/5 and efflux transporter P-gp, so drug-drug interactions may occur during their co-administration treatment. Therefore, this study aimed to evaluate the pharmacokinetic interaction between imatinib and tacrolimus in rats. METHODS: Rats were divided into groups I (30 mg/kg imatinib administered for 14 days), II (1.89 mg/kg tacrolimus and 30 mg/kg imatinib administered for 14 days), III (30mg/kg imatinib and 0.63mg/kg tacrolimus administered for 14 days), IV (1.89mg/kg tacrolimus for 14 days), and V (10mg/kg imatinib and 1.89mg/kg tacrolimus for 14 days). Blood samples were determined for whole blood of tacrolimus, plasma of imatinib, and Ndesmethyl imatinib concentrations using ultra-performance liquid chromatography-mass spectrometry. RESULTS: After 1 day of a single dose, tacrolimus had no significant effect on the pharmacokinetics of imatinib and N-desmethyl imatinib; imatinib significantly increased the AUC and C of tacrolimus (P < 0.05). After 14 days of multiple doses, tacrolimus significantly reduced the AUC and C of imatinib and N-desmethyl imatinib (P < 0.05). Further, imatinib significantly increased AUC and AUC of tacrolimus (P < 0.05). CONCLUSION: Imatinib increased tacrolimus blood concentrations after single and multiple administrations. Tacrolimus did not significantly affect the pharmacokinetics of imatinib after a single dose; however, tacrolimus might impact the absorption and metabolism of imatinib after multiple doses. The results showed that when imatinib and tacrolimus were co-administered, attention should be paid to the presence of drug-drug interactions.
Characterizing Pharmacokinetic Variability of Topiroxostat in Chinese Population: Insights from a Phase I Randomized Clinical Trial.
Zhong T, Huang K, Han L … +6 more , Pang W, Xia Y, Qu S, Yu G, Chen Y, Fan H
Curr Drug Metab · 2025 · PMID 39686641 · Publisher ↗
OBJECTIVE: This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects. METHOD...
OBJECTIVE: This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects. METHODS: The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition. RESULTS: Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79-0.98 h) than in males (0.53-0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h. CONCLUSION: The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.
Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies.
Yan Y, Guo Y, Wang Z … +5 more , He W, Zhu Y, Zhao X, Sun L, Wang Y
Curr Drug Metab · 2025 · PMID 39620327 · Publisher ↗
Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its s...
Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.
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