CYP3A4 Inhibitor Research Articles

An Evaluation of Iloperidone for Mania in Bipolar I Disorder.

To review the efficacy of iloperidone for mania associated with bipolar I disorder and discuss its safety profile (eg, QTc prolongation, orthostatic hypotension, and metabolic adverse effects). Literature was identified using PubMed (1966-September 2024), OVID (1984-November 2024), and clinicaltrials.gov. Search terms included iloperidone, bipolar disorder, and mania. The study included trials evaluating iloperidone for treating bipolar mania. In one phase 3 study, iloperidone demonstrated significant improvement in mania symptoms at day 28 on all primary (ie, Young Mania Rating Scale) and secondary outcomes (Clinical Global Impression-Severity/Change scales) compared to placebo. Iloperidone was well tolerated, with tachycardia, dizziness, dry mouth, alanine aminotransferase elevation, nasal congestion, increased weight, and somnolence reported as common adverse effects. Since there are no head-to-head studies comparing iloperidone with other second-generation antipsychotics for bipolar mania, other treatment considerations drive medication selection. Iloperidone is unavailable in a generic formulation; thus, its use will be associated with higher costs. It is dosed twice daily, which may negatively impact adherence. Iloperidone is associated with a moderate risk of QTc prolongation, metabolic adverse effects, and orthostatic hypotension, which will limit its use in certain patient populations. QTc prolongation is dose related, so drug interactions involving CYP2D6 and CYP3A4 inhibition can have serious consequences. In the pivotal trial, iloperidone was effective in treating adults with an acute manic or mixed episode associated with bipolar I disorder and was safe and well tolerated.

Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.

A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R2 side-group and R3 end-group interplay when the R1 side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R1/R2-phenyl inhibitors upon elongation and/or fluorination of R3-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R3 is pyridine, the impact of R2-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R2-naphthalene/R3-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (Ks = 0.009 μM; IC50 = 0.10 μM). Introduction of a larger biphenyl or fluorene as R2 did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (Ks = 0.734 μM; IC50 = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R2-biphenyl, however, can switch positions with R3-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R2/R3 interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.

Effects of fluconazole on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes.

This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200mg celecoxib. In the celecoxib with fluconazole trial, participants received 300mg fluconazole on day 1, 150mg fluconazole once daily for four consecutive days (day 2-5), and a coadministration of 200mg celecoxib with 150mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC-MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.44-fold (p < 0.001), prolonged t1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUCinf of celecoxib by 2.23-fold, prolonged t1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. Cmax of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUCinf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.

Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions.

Ritonavir (RTV) is a potent CYP3A inhibitor that is widely used as a pharmacokinetic (PK) enhancer to increase exposure to select protease inhibitors. However, as a strong and complex perpetrator of CYP3A interactions, RTV can also enhance the exposure of other co-administered CYP3A substrates, potentially causing toxicity. Therefore, the prediction of drug-drug interactions (DDIs) and estimation of dosing requirements for concomitantly administered drugs is imperative. In this study, we aimed to develop a physiologically-based PK (PBPK) model for RTV using the PK-sim® software platform. A total of 13 clinical PK studies of RTV covering a wide dose range (100 to 600 mg including both single and multiple dosing), and eight clinical DDI studies with RTV on CYP3A and P-gp substrates, including alprazolam, midazolam, rivaroxaban, clarithromycin, fluconazole, sildenafil, and digoxinwere used for the model development and evaluation. Chronopharmacokinetic differences (between morning vs. evening doses) and limitations in parameter estimation for biochemical processes of RTV from invitro studies were incorporated in the PBPK model. The final developed PBPK model predicted 100% of RTV AUClast and Cmax within a twofold dimension error. The geometric mean fold error (GMFE) from all PK datasets was 1.275 and 1.194, respectively. In addition, 97% of the DDI profiles were predicted with the DDI ratios within a twofold dimension error. The GMFE values from all DDI datasets were 1.297 and 1.212, respectively. Accordingly, this model could be applied to the prediction of DDI profiles of RTV and CYP3A substrates and used to estimate dosing requirements for concomitantly administered drugs.

Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants.

Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor. Geometric least-squares mean ratios and 90% confidence intervals for maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) were obtained. Safety was monitored throughout the studies. All adverse events were mild or moderate in severity. Seralutinib coadministration increased AUC for midazolam 3.03-fold and caffeine 1.32-fold. The coadministration increased digoxin Cmax 1.28-fold. Seralutinib did not meaningfully alter Cmax and AUC for montelukast, flurbiprofen, or pravastatin. Fosaprepitant and itraconazole increased seralutinib AUC 1.08- and 1.84-fold, respectively. Seralutinib is a moderate CYP3A inhibitor and a weak CYP1A2 inhibitor; it slightly inhibits P-gp. Seralutinib exposure is minimally affected by a weak CYP3A inhibitor but is substantially increased by a strong CYP3A inhibitor.

Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor.

This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600mg dose (1µCi [14C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600mg twice daily. Plasma, urine, and feces were collected post [14C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib's potential to inhibit CYP enzymes and identify CYPs involved in its metabolism. The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4. Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.

Static Versus Dynamic Model Predictions of Competitive Inhibitory Metabolic Drug-Drug Interactions via Cytochromes P450: One Step Forward and Two Steps Backwards.

Predicting metabolic drug-drug interactions (DDIs) via cytochrome P450 enzymes (CYP) is essential in drug development, but controversy has reemerged recently about whether in vitro-in vivo extrapolation (IVIVE) using static models can replace dynamic models for some regulatory filings and label recommendations. The aim of this study was to determine if static and dynamic models are equivalent for the quantitative prediction of metabolic DDIs arising from competitive CYP inhibition. Drug parameter spaces were varied to simulate 30,000 DDIs between hypothetical substrates and inhibitors of CYP3A4. Predicted area under the plasma concentration-time profile ratios for substrates (AUCr = AUC(presence of precipitant)/AUC(absence of precipitant)) were compared between dynamic simulations (Simcyp® V21) and corresponding static calculations, giving an inter-model discrepancy ratio (IMDR = AUCrdynamic/AUCrstatic). Dynamic simulations were conducted using a 'population' representative and a 'vulnerable patient' representative with maximal concentration (Cmax) or average steady-state concentration (Cavg,ss) as the inhibitor driver concentrations. IMDRs outside the interval 0.8-1.25 were defined as discrepancy between models. The highest rate of IMDR <0.8 and IMDR >1.25 discrepancies in the 'population' representative was 85.9% and 3.1%, respectively, when using Cavg,ss as the inhibitor driver concentration. Using the 'vulnerable patient' representative showed the highest rate of IMDR >1.25 discrepancies at 37.8%. Static models are not equivalent to dynamic models for predicting metabolic DDIs via competitive CYP inhibition across diverse drug parameter spaces, particularly for vulnerable patients. Caution is warranted in drug development if static IVIVE approaches are used alone to evaluate metabolic DDI risks.

In Vitro and In Silico Biological Activities Investigation of Ethyl Acetate Extract of Rubus ulmifolius Schott Leaves Collected in Algeria.

This investigation aimed to assess the in vitro and in silico biological properties of the ethyl acetate (EtOAc) extract obtained from leaves of Rubus ulmifolius Schott collected in Algeria. The phytochemical screening data disclosed that flavonoids, tannins, coumarins, saponins, and anthocyanins were abundant. High levels of total phenolics, total flavonoids and flavonols (523.25 ± 3.53 µg GAE/mg, 20.41 ± 1.80, and 9.62 ± 0.51 µg QE/mg respectively) were detected. Furthermore, GC-MS analysis was performed to identify low molecular weight compounds. d-(-)-Fructofuranose, gallic acid, caffeic acid, and catechin were detected as main metabolites of the EtOAc extract. The outcomes revealed that the extract exerted a potent antioxidant apt, and ensured significant bacterial growth inhibitory capacity, where the inhibition zone diameters ranged from 20.0 ± 0.5 to 24.5 ± 0.3 mm. These outcomes were confirmed through molecular docking against key bacterial enzymes that revealed significant interactions and binding affinities. d-(-)-Fructofuranose was identified as the most polar and flexible compound. Gallic acid and caffeic acid demonstrated higher unsaturation. Caffeic acid was well absorbed in the blood-brain barrier (BBB) and human intestine. Catechin was well absorbed in CaCO3, and can act as an inhibitor of CYP1A2. These results highlight how crucial it is to keep looking into natural substances in the quest for more potent and targeted pathology therapies.

CYP3A4 drug metabolism considerations in pediatric pharmacotherapy

AbstractCytochrome P450 3A4 (CYP3A4) is a crucial enzyme involved in the Phase I metabolism of numerous medications used in clinical practice. Its potential significance in pediatric pharmacotherapy is underscored by the unique metabolic profile of children, which differs markedly from adults, especially in neonates, infants, and young children due to developmental changes in enzyme activity. This review explores the critical role of CYP3A4 in the metabolism of drugs used in the pediatric population, with a particular focus on combination drug therapies. Given the high potential for drug-drug interactions in combination therapies, understanding the modulation of CYP3A4 activity is essential for optimizing therapeutic outcomes and minimizing adverse effects. This paper further examines the structural similarities between these medications and bergamottin, a known CYP3A4 inhibitor found in citric fruits such as grapefruit. Variability in CYP3A4 activity, influenced by genetic polymorphisms, developmental stage, and external factors, necessitates careful consideration in the prescribing and management of drugs in children. This review corroborates the need for personalized medicine approaches and enhanced pharmacovigilance to ensure the safe and effective use of CYP3A4-metabolized drugs in the pediatric population. Graphical Abstract

A novel in vivo approach to monitoring Cyp3a induction and inhibition by bioluminescent urinalysis

ABSTRACT Background Adverse drug–drug interactions (DDI) may occur when one drug accelerates or slows a second drug’s metabolism by, respectively, inducing or inhibiting a cytochrome P450 (CYP) that metabolizes that second drug. We developed an in vivo method employing urinalysis to complement in vitro CYP induction and inhibition measurements widely used to predict DDIs. Research design and methods Focusing on Cyp3a enzymes, the major mammalian drug metabolizers, we applied luciferin-IPA, a selective Cyp3a probe substrate to mice after Cyp3a inducers and inhibitor treatments. Cyp3a converts the probe to a metabolite that is eliminated in urine and drives light output when mixed with a luciferase reaction mixture. We hypothesized that urine from an initial renal elimination phase would, respectively, drive elevated or reduced light output as a reflection of Cyp3a induction or inhibition. Results Luciferase mixed with urine from Cyp3a-induced mice showed enhanced signals, while a Cyp3a inhibitor diminished induced and basal signals versus vehicle. Conclusions A Cyp3a-selective luminogenic probe substrate enables rapid urinalysis-based testing for detecting Cyp3a induction and inhibition and predicting Cyp3a-dependent DDIs. The study serves as a proof of concept for using caged luciferins for in vivo enzyme activity tests with a readily accessible sample type.

Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies

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.

A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus.

One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (Cmax) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.

Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug-Drug Interactions.

Adagrasib is a potent, highly selective, orally available, small molecule, covalent inhibitor of G12C mutated KRAS. As both a substrate and strong inhibitor of cytochrome P450 (CYP) 3A4, adagrasib inhibits its own CYP3A4-mediated metabolism following multiple dosing, resulting in time-dependent drug-drug interaction (DDI) liabilities. A physiologically-based pharmacokinetic (PBPK) model was developed and verified using a combination of physicochemical, in vitro and clinical pharmacokinetic (PK) data from healthy volunteers and cancer patients. The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested scenarios including the clinical victim and perpetrator DDI liabilities at the approved dosing regimen of 600 mg twice daily (b.i.d.) in cancer patients. Strong, moderate, and weak inhibitors of CYP3A4 are predicted to have a negligible effect on the steady-state exposure of adagrasib 600 mg b.i.d. resulting from the significant inactivation of CYP3A4 by adagrasib. Additionally, strong and moderate inducers of CYP3A4 are predicted to decrease adagrasib exposure by 68% and 22%, respectively. As a perpetrator, adagrasib 600 mg b.i.d. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.

Analyzing the Effect of Resveratrol on Pharmacokinetics of Antituberculosis Drug Bedaquiline in Rats by a Novel UPLC-MS/MS Approach.

Bedaquiline (BDQ), a diarylquinoline compound, is an inhibitor of mycobacterial ATP synthase, specifically with FDA approval as a treatment for multidrug-resistant tuberculosis (MDR-TB). M2 is the main metabolite of BDQ and is active against tuberculosis. The objective of this study was to establish and validate a sensitive and convenient ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach to concurrently quantify BDQ and M2 in rat plasma and to examine whether resveratrol, a CYP3A4 inhibitor, could influence the pharmacokinetics of BDQ and M2 in rats. Plasma samples containing the internal standard (IS) linezolid were formulated by adding acetonitrile for a simple one-step protein precipitation, and the analytes in samples were quantified by the UPLC-MS/MS method. BDQ and M2 were successfully calibrated in the ranges of 0.5-1000 and 1.0-200 ng/mL, where the lower limit of quantification (LLOQ) was 0.5 and 1.0 ng/mL, respectively. The precisions and accuracies of BDQ and M2 were in compliance with the FDA analytical standards. Recoveries and matrix effects of the analytes were satisfactory, and the analytes remained stable under four different temperatures and conditions. The well-validated UPLC-MS/MS method was successfully applied to the study of the food-drug interaction in rats. Remarkably, resveratrol increased the level of exposure of BDQ. Furthermore, the effect of resveratrol on the metabolism of BDQ and M2 needs further clinical studies.

MANAGEMENT OF ANTICOAGULATION IN ATRIAL FIBRILLATION: MINIMIZING DRUG INTERACTIONS WITH DOACS

Introduction: Atrial fibrillation (AF) is a common cardiac arrhythmia that elevates the risk of thromboembolic events, necessitating effective anticoagulation strategies. Direct oral anticoagulants (DOACs) have become the preferred choice due to their safety profiles; however, drug interactions can compromise their efficacy and safety. Objective: This study aims to assess the impact of drug interactions on the efficacy and safety of DOACs in patients with AF. Method: A literature review was conducted using databases such as the Virtual Health Library, LILACS Plus, and Medline, focusing on articles published from 2019 to 2024. Inclusion criteria emphasized studies related to drug interactions involving DOACs and AF, resulting in the selection of 13 relevant articles. Results: The analysis revealed a significant prevalence of drug interactions among patients treated with DOACs. Co-prescription with CYP3A4 inhibitors and P-glycoprotein modulators was linked to increased bleeding risks. Factors such as age, renal function, and the presence of comorbidities were crucial in determining appropriate dosing and the risk of adverse events. Conclusion: Careful management of AF patients on DOACs is vital to mitigate risks associated with drug interactions. Personalized treatment approaches that consider individual clinical profiles and ongoing education for healthcare providers are essential to optimize anticoagulation therapy.

In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers.

Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (Cmax) and area under the curve from time of dosing extrapolated to infinity (AUCinf) to 182% and 939%, respectively, while ES259564 Cmax decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant Cmax and AUCinf decreased to 71.7% and 48.3%, respectively, while ES259564 Cmax increased to 130.2% and AUCinf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.

Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.

Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC-MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.

Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms.

Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision-recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.

The Effect of Ketoconazole and Quinestrol Combination on Reproductive Physiology in Male Mice.

This study investigates whether ketoconazole, a CYP3A4 inhibitor, can enhance the suppressive effects of quinestrol on reproductive capacity, potentially allowing for a reduced quinestrol dosage while maintaining its efficacy. A total of 104 healthy adult male mice were divided into two groups, assessed at 10 and 30 days. Within each group, six treatment categories were tested: the control (CK), quinestrol alone (Q1, Q5), and quinestrol combined with varying doses of ketoconazole (Q1 + K0.4, Q1 + K2, Q5 + K0.4). The key parameters measured included internal and reproductive organ weights, sperm density, sperm motility, sperm abnormalities, and CYP3A4 enzyme content in intestinal and liver tissues. After 10 days, the combination of a low dose of quinestrol with ketoconazole (Q1 + K0.4) showed the most significant pronounced effects in reducing reproductive potential, with notable reductions in epididymal weight, sperm density, sperm abnormality rate and vitality, serum hormone levels, and CYP3A4 content in the small intestine and liver. Although some reproductive parameters returned to near-baseline levels after 30 days, the Q1 + K0.4 regimen continued to exhibit reduced seminal vesicle weight and testosterone levels. Importantly, the combination did not significantly increase CYP3A4 enzyme content, indicating effective metabolic inhibition. The combination of quinestrol and ketoconazole, especially the Q1 + K0.4 regimen, demonstrated the most noticeable impact on reducing reproductive capacity. This regimen significantly reduced key reproductive parameters and showed strong metabolic inhibition, suggesting that ketoconazole substantially enhances the efficacy of quinestrol in fertility control.

The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation.

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.