Explore the vast range of titles available.

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

The anticonvulsant carbamazepine is frequently used in the long-term therapy of epilepsy and is a known substrate and inducer of cytochrome P450 (CYP) 3A4 and CYP2B6. Carbamazepine induces the metabolism of various drugs (including its own); on the other hand, its metabolism can be affected by various CYP inhibitors and inducers. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) parent−metabolite model of carbamazepine and its metabolite carbamazepine-10,11-epoxide, including carbamazepine autoinduction, to be applied for drug–drug interaction (DDI) prediction. The model was developed in PK-Sim, using a total of 92 plasma concentration−time profiles (dosing range 50–800 mg), as well as fractions excreted unchanged in urine measurements. The carbamazepine model applies metabolism by CYP3A4 and CYP2C8 to produce carbamazepine-10,11-epoxide, metabolism by CYP2B6 and UDP-glucuronosyltransferase (UGT) 2B7 and glomerular filtration. The carbamazepine-10,11-epoxide model applies metabolism by epoxide hydroxylase 1 (EPHX1) and glomerular filtration. Good DDI performance was demonstrated by the prediction of carbamazepine DDIs with alprazolam, bupropion, erythromycin, efavirenz and simvastatin, where 14/15 DDI AUClast ratios and 11/15 DDI Cmax ratios were within the prediction success limits proposed by Guest et al. The thoroughly evaluated model will be freely available in the Open Systems Pharmacology model repository.

•Vepdegestrant is a PROteolysis TArgeting Chimera estrogen receptor degrader.•Coadministration with itraconazole increased vepdegestrant exposure by 69%.•CYP3A4 is involved, albeit not predominantly, in vepdegestrant elimination. Vepdegestrant (ARV-471) is an orally administered PROteolysis TArgeting Chimera estrogen receptor (ER) degrader that directly binds an E3 ligase and ER to trigger ubiquitination and subsequent proteasomal degradation of ER. Based on findings from a first-in-human phase 1/2 trial, vepdegestrant 200 mg once daily was selected as the recommended phase 3 dose and was evaluated in the phase 3 clinical study VERITAC-2 (NCT05654623) for the treatment of patients with ER-positive human epidermal growth factor receptor 2–negative breast cancer. Vepdegestrant is a substrate of cytochrome P450 (CYP)3A4 in vitro; therefore, its plasma exposure may increase when coadministered with CYP3A4 inhibitors, such as the strong index CYP3A4 inhibitor itraconazole. This study evaluated the effect of itraconazole on the pharmacokinetics (PK) and safety of vepdegestrant in healthy adults. During this phase 1, open-label, 2-period, fixed-sequence study (NCT05538312), participants received 2 doses of vepdegestrant and multiple doses of itraconazole. In period 1, participants received a single dose of vepdegestrant 200 mg under fed conditions followed by a washout period of at least 10 days. In period 2, participants received itraconazole 200 mg once daily under fasted conditions on days 1–11 and a single dose of vepdegestrant 200 mg under fed conditions on day 5 with concomitant itraconazole administration. Plasma samples were collected predose and serially following each vepdegestrant dose. PK parameters calculated for vepdegestrant and its epimer metabolite, ARV-473, included area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax). Safety was monitored throughout the study. A total of 12 healthy adult participants received vepdegestrant with (test) and without (reference) itraconazole. The vepdegestrant test/reference ratios of the adjusted geometric means (90% confidence intervals) for AUCinf and Cmax were 168.9% (157.7–180.9) and 152.2% (136.9–169.2), respectively. Similar increases in exposure were observed for ARV-473. All adverse events were mild or moderate, and no participants discontinued from the study due to adverse events. Coadministration of multiple doses of itraconazole, a strong CYP3A4 inhibitor, increased vepdegestrant exposure by 69%, suggesting the involvement of CYP3A4-mediated metabolism, albeit not predominantly, in vepdegestrant elimination.

•TPN171 is a self-developed PDE5 inhibitor used to treat Pulmonary arterial hypertension and erectile dysfunction with the advantages of high activity, good selectivity, low toxicity, rapid oral absorption, and long half-life in vivo.•The Cmax and AUC0-∞ for TPN171 were increased by 76.00% and 185.67% when combined with itraconazole versus TPN171 alone, and reduced by 74.53% and 90.14% when combined with rifampin versus TPN171 alone.•Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects.•TPN171 demonstrated a favorable safety profile and was well-tolerated in healthy subjects, whether administered as monotherapy or co-administered with the CYP3A4 inhibitor itraconazole or inducer rifampicin.•TPN171 exhibits a significant interaction with CYP3A4 inhibitors/inducers. TPN171, a novel, highly selective, and potent phosphodiesterase type 5 (PDE5) inhibitor, is currently under clinical development for the treatment of pulmonary arterial hypertension (PAH) and erectile dysfunction (ED). The drug is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4. We evaluated the pharmacokinetic (PK) profile and safety of TPN171, both alone and in combination with itraconazole (a CYP3A4 potent inhibitor) or rifampin (a CYP3A4 potent inducer), in healthy Chinese volunteers. In this open-label, fixed-sequence study, TPN171 (10 mg) was administered orally once daily on Days 1 and 6 in Cohort 1, followed by oral itraconazole (200 mg) once daily from Days 3 to 6. Cohort 2 received oral TPN171 (20 mg) once daily on Days 1 and 10, with concurrent oral rifampin (600 mg) once daily administered from Days 3 to 10. Twenty-four healthy subjects were enrolled (12 per cohort). The PK parameters of TPN171 were estimated through noncompartmental analysis with its plasma concentration detection. Comparisons of the maximum plasma concentration (Cmax) and the area under the concentration–time curve extrapolated to infinity (AUC0-∞) for TPN171 were conducted between conditions with and without coadministration of itraconazole or rifampin. The Cmax and AUC0-∞ for TPN171 were increased by 76.00% (least squares geometric mean ratios (LSGMR), 176.00% [90% CI, 160.37%–193.15%]) and 185.67% (LSGMR, 285.67% [90% CI, 261.87%–311.64%]) when combined with itraconazole versus TPN171 alone. The Cmax and AUC0-∞ of TPN171 were reduced by 74.53% (LSGMR, 25.47% [90% CI, 21.98%–29.50%]) and 90.14% when combined with rifampin versus TPN171 alone (LSGMR, 9.86% [90% CI, 9.08%–10.71%]). Spontaneous penile erection was the most frequently reported adverse event, occurring in 17 (70.83%) of the 24 subjects. CYP3A4 potent inhibitors and inducers can significantly affect the exposure level of TPN171, especially the inducers. Therefore, when taking TPN171, it is recommended to avoid concomitant administration with CYP3A4 potent inhibitors or potent/moderate inducers, or adjust the dosage of TPN171.

Cytochrome P450 3A4 (CYP3A4) is a membrane bound monooxygenase. It metabolizes the largest proportion of all orally ingested drugs. Ligands can enter and exit the enzyme through flexible tunnels, which co-determine CYP3A4’s ligand promiscuity. The flexibility can be represented by distinct conformational states of the enzyme. However, previous state definitions relied solely on crystal structures. We employed conventional molecular dynamics (cMD) simulations to sample the conformational space of CYP3A4. Five conformationally different crystal structures embedded in a membrane were simulated for 1 µs each. A Markov state model (MSM) coupled with spectral clustering (Robust Perron Cluster Analysis PCCA +) resulted in three distinct states: Two open conformations and an intermediate conformation. The tunnels inside CYP3A4 were calculated with CAVER3.0. Notably, we observed variations in bottleneck radii compared to those derived from crystallographic data. We want to point out the importance of simulations to characterize the dynamic behaviour. Moreover, we identified a mechanism, in which the membrane supports the opening of a tunnel. Therefore, CYP3A4 must be investigated in its membrane-bound state.

Cytochrome P450 3A4 (CYP3A4) enzyme activity is known to show considerable ethnic heterogeneity and inter-individual differences, affecting the outcome of drug treatment. genetic polymorphisms are believed to be one of the important causes, leading to inter-individual variability in drug metabolism. Quinine is an antipyretic drug with antimalarial properties that is metabolized primarily by CYP3A4. Quinine 3-hydroxylation has been proven as a biomarker reaction for evaluating CYP3A4 ability. Quinine has frequent adverse effects and there are distinct inter-individual differences in quinine sensitivity. The open reading frame for 30 allelic variants were constructed from wild-type by an overlap extension polymerase chain reaction. Recombinant CYP3A4 variants were expressed using baculovirus-insect cell expression system, and their catalytic activities towards quinine hydroxylation were determined and evaluated. Of the 30 CYP3A4 allelic variants, 23 variants exhibited significantly reduced intrinsic clearance towards quinine, 2 variants showed increased intrinsic clearance for quinine, 2 variants possessed no significant differences towards quinine, compared with CYP3A4*1A, and 3 variants had no detected expression and enzyme activity. Our assessment on the enzymatic activities of CYP3A4 variants towards quinine may contribute to laying an experimental foundation for further clinical studies so as to accelerate the process of determining the associations between genetic variations and clinical phenotypes.

Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would affect asthma outcomes. Patients aged 2–18 years with persistent asthma were recruited to use the electronic AsthmaTracker (e-AT), a self-monitoring tool that records weekly asthma control, medication use, and asthma outcomes. A subset of patients provided saliva samples for SNP analysis and participated in a pharmacokinetic study. Multivariable regression analysis adjusted for age, sex, race, and ethnicity was used to evaluate the impact of CYP3A5 SNPs on asthma outcomes, including asthma control (measured using the asthma symptom tracker, a modified version of the asthma control test or ACT), exacerbations, and hospital admissions. Plasma corticosteroid and cortisol concentrations post-ICS dosing were also assayed using liquid chromatography–tandem mass spectrometry. Of the 751 patients using the e-AT, 166 (22.1%) provided saliva samples and 16 completed the PK study. The e-AT cohort was 65.1% male, and 89.6% White, 6.0% Native Hawaiian, 1.2% Black, 1.2% Native American, 1.8% of unknown race, and 15.7% Hispanic/Latino; the median age was 8.35 (IQR: 5.51–11.3) years. CYP3A5*3/*3 frequency was 75.8% in White subjects, 50% in Native Hawaiians and 76.9% in Hispanic/Latino subjects. Compared with CYP3A5*3/*3, the CYP3A5*1/*x genotype was associated with reduced weekly asthma control (OR: 0.98; 95% CI: 0.97–0.98; p < 0.001), increased exacerbations (OR: 6.43; 95% CI: 4.56–9.07; p < 0.001), and increased asthma hospitalizations (OR: 1.66; 95% CI: 1.43–1.93; p < 0.001); analysis of 3/*3, *1/*1 and *1/*3 separately showed an allelic copy effect. Finally, PK analysis post-ICS dosing suggested muted changes in cortisol concentrations for patients with the CYP3A5*3/*3 genotype, as opposed to an effect on ICS PK. Detection of CYP3A5*3/3, CYPA35*1/*3, and CYP3A5*1/*1 could impact inhaled steroid treatment strategies for asthma in the future.

Objective To analyze the lipid composition of coronary endarterectomy (CE) plaques and explore the mechanisms affecting the mid- and long-term efficacy of CE. Methods Sixteen patients matched out of fifty patients with diffuse coronary artery disease performing coronary artery bypass grafting (CABG) with endarterectomy were enrolled from Beijing Anzhen Hospital between January 2024 and May 2024. Patients were divided into high-risk and low-risk groups to detect plaque tissue and CYP3A4 content, and analyze the restenosis rate by CATCH technique. Mendelian randomization consisting of univariate, mediation and sensitivity analysis were conducted to figure out the causal correlation. Results Lipidomics revealed significantly higher level of 4α-hydroxycholesterol (4αOH-CHO) in the high-risk group (0.050 μmol/g vs. 0.016 μmol/g, P < 0.05). Plasma CYP3A4 levels in the experimental group were higher immediate and in long term. A better long-term patency in the control group was discovered [stenosis rate (9.0 ± 1.9)% vs. (22.3 ± 2.3)%, P < 0.05)]. Genetical evidence showcased a causal relationship between hydroxycholesterol with atherosclerosis (AS) (P = 0.014), and increased CYP3A4 content may be due to the existing AS (P = 0.003). Conclusion High expression of 4αOH-CHO may accelerate AS and cause mid- and long-term restenosis after CE. In AS population, 4αOH-CHO may be identified as a practical marker of CYP3A4, assessing the progression mechanisms of AS after CE.

PurposeThe benefits of statins for ischemic cardio-cerebrovascular diseases are well known. However, concerns around muscle adverse events still exist. We therefore aimed to compare the muscle safety of individual statins in adults.MethodsPubMed, Embase, Cochrane Central Register of Controlled Trials and Web of Science were searched to include double-blind randomized controlled trials (RCTs) comparing one statin with another or with control treatment. Pairwise meta-analyses and network meta-analyses were undertaken with Stata 14.0 software. Relative risk (RR) with 95% confidence intervals (CIs) was adopted for each outcome.ResultsA total of 83 RCTs were included. In the pairwise meta-analysis, statins were significantly associated with only a slight increase in muscle symptoms compared with control (RR=1.05; 95% CI=1.01–1.09). In the drug-level network meta-analyses, no statistically significant difference was found between individual statins in the incidence of muscle symptoms, myalgia, myopathy, rhabdomyolysis, creatine kinase (CK) >10 times the upper limit of normal (ULN) or discontinuation due to muscle adverse events. In the dose-level network meta-analyses, there were no statistically significant dose-dependent effects on any outcomes except that moderate-intensity statins had a higher incidence of muscle symptoms than control (RR=1.13; 95% CI=1.01–1.27). Moderate simvastatin (RR=6.57; 95% CI=1.26–34.41) and moderate pravastatin (RR=5.96; 95% CI=1.00–35.44) had a statistically significantly higher incidence of CK >10×ULN compared with moderate atorvastatin. Lipophilic statins and statins metabolized by liver cytochrome P450 3A4 were not associated with an increased risk of muscle adverse events.ConclusionStatins may be generally safe on muscle. Moderate atorvastatin may be superior to equivalent simvastatin and pravastatin in muscle tolerability.

The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug–drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug–drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4’s role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide’s regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug–drug interactions and hinder the hepatic metabolism of ivermectin.