CYP3A4 Inhibitor Research Articles

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.

Drug-Drug Interaction Management with the Novel Anti-Cytomegalovirus Agents Letermovir and Maribavir: Guidance for Clinicians.

Letermovir and maribavir have demonstrated efficacy in the prevention and treatment, respectively, of immunosuppressed patients with cytomegalovirus (CMV) infection and disease. These patients often have polypharmacy making them at risk for drug-drug interactions. Both letermovir and maribavir can be perpetrators and victims of drug-drug interactions. Letermovir is a moderate inhibitor of CYP3A, CYP2C8 and OATP1B1/3, and a moderate inducer of CYP2C19. It is a substrate of UGT1A1/3, BCRP, P-gp and OATP1B1/3. Maribavir is a moderate CYP2C9 inhibitor and a substrate of CYP3A. Drug-drug interactions between these anti-CMV agents and a number of therapeutic classes, such as immunosuppressants, antifungal agents, and hemato-oncological agents, can have clinical consequences and deserve dose modification or close monitoring. In a number of examples, three-way drug interactions need to be assessed. The objective of this review is to provide clinicians with guidance for drug-drug interaction management, based on existing data from drug-drug interaction studies, and extrapolation to other relevant co-medications that have not (yet) been studied but that are frequently used in these patient populations.

Clozapine Toxicity Predictor: Deep neural network model predicting clozapine toxicity and its therapeutic dose range

Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients with treatment-refractory patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop.

Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects.

SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

Heterotropic Allosteric Modulation of CYP3A4 In Vitro by Progesterone: Evidence for Improvement in Prediction of Time Dependent Inhibition for Macrolides.

Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mis-predicted (i.e. false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex (MIC) forming inhibitors. The impact of the presence of 100 µM PGS on the TDI of molecules in the class of macrolides typically associated with MIC formation was investigated. Presence of PGS resulted in varied responses across the inhibitors tested. The TDI signal was eliminated for five inhibitors, and unaltered in the case of one, fidaxomicin. The remaining molecules erythromycin, clarithromycin, and troleandomycin, were observed to have a decrease in both potency and maximum inactivation rate ranging from 1.7-fold to 6.7-fold. These changes in TDI kinetics led to a >90% decrease in inactivation efficiency. In order to determine in vitro conditions that could reproduce in vivo inhibition, varied concentrations of PGS were incubated with clarithromycin and erythromycin. Resulting in vitro TDI kinetics were incorporated into dynamic physiologically-based pharmacokinetic (PBPK) models to predict clinically observed interactions. The results suggested that a concentration of ~45 µM PGS would result in TDI kinetic values that could reproduce in vivo observations and could potentially improve predictions for CYP3A4 TDI. Significance Statement The impact of the allosteric heterotropic modulator progesterone on the CYP3A4 time-dependent inhibition kinetics was quantified for a set of metabolic-intermediate complex forming mechanism-based inhibitors. We identify the in vitro conditions that optimally predict time-dependent inhibition for in vivo drug-drug interactions through dynamic physiologically-based pharmacokinetic modeling. The optimized assay conditions improve in vitro to in vivo translation and prediction of time-dependent inhibition.

Coadministration of Cariprazine with a Moderate CYP3A4 Inhibitor in Patients with Schizophrenia: Implications for Dose Adjustment and Safety Monitoring.

Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Erythromycin increased the area under the curve (AUCτ) and peak concentration (Cmax) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40-50% but did not affect the time to peak concentration (Tmax). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

Inhibitory effects characteristics of polysaccharide of Polygonati Rhizome on cytochrome P450 enzymes.

As the major active ingredient of Polygonatum sibriricum Red., polysaccharide of Polygonati Rhizome (PSP) has been reported to possess various pharmacological activities, especially for the treatment of chronic disorders in the elderly. This study evaluated the effect of PSP on the activities of major cytochrome P450 enzymes (CYP450) isoforms, aiming to provide theoretical reference for its co-prescription with other drugs and prevent the risk of adverse drug-drug interaction. The activities of CYP450 isoforms were assessed in human liver microsomes with specific probe substances. Through Lineweaver-Burk fitting models, the effect of PSP on the activity of inhibited CYP450 isoforms was characterized by competitive and non-competitive models. Dose-dependent and time-dependent experiments were also performed to completely understand the inhibition. Among experimental isoforms, PSP significantly inhibited the activities of CYP2C9, 2D6, and 3A4 in a concentration-dependent manner with IC50 values of 14.01, 17.63, and 5.33 μM. The inhibition of CYP2C9 and 2D6 was best fitted with the competitive model with the Ki values of 7.15 and 8.92 μM, respectively, while the inhibition of CYP3A4 was non-competitive with the Ki value of 2.63 μM. Additionally, the inhibition of CYP3A4 by PSP also showed time-dependent characteristics with the inhibition parameters, KI of 1.273 μM-1 and Kinact of 0.036 min-1. PSP exerted moderate inhibition on CYP2C9 and 2D6 and strong inhibition of CYP3A4. The dosage of CYP2C9-, 2D6-, and 3A4-metabolized drugs should be adjusted when co-administrated with PSP and its sourced herbs.

Early Prediction and Impact Assessment of CYP3A4-Related Drug-Drug Interactions for Small-Molecule Anticancer Drugs Using Human-CYP3A4-Transgenic Mouse Models.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method. SIGNIFICANCE STATEMENT: The described method offers an alternative for the early detection and assessment of potential clinical impact of CYP3A4-related drug-drug interactions. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer.

Risks of Tacrolimus and Paxlovid Therapy in SARS-CoV-2 Positive Transplant Recipients: A Case Discussion and Institutional Data Review

Abstract Introduction/Objective Transplant recipients maintained on immunosuppressants like tacrolimus continue to be at high risk for morbidity due to SARS-CoV-2 infection and are strong candidates for antiviral therapies. However, co- administration of the antiviral Paxlovid (nirmatrelvir/ritonavir) poses a significant risk to these patients due to ritonavir- mediated inhibition of CYP3A, an important mediator of tacrolimus metabolism. Consequently, Paxlovid therapy in post-organ transplant patients on tacrolimus requires careful consideration. Our investigation aims to assess the continuing risk posed by this drug-drug interaction and better understand clinical circumstances linked to critically high tacrolimus levels due to Paxlovid co-administration. Methods/Case Report We conducted a large-scale retrospective analysis of tacrolimus measurements at the University of Michigan Medicine beginning in January 2020. We also performed a detailed review of patients with critically high tacrolimus levels coinciding with Paxlovid administration. Results (if a Case Study enter NA) Of 39,752 tacrolimus measurements examined, 682 correspond to 329 patients with recent positive SARS-CoV-2 nucleic acid testing, and 37 correspond to 18 patients with documented Paxlovid co- administration. Patients receiving concurrent Paxlovid and tacrolimus demonstrate 1.6- and 1.8-fold higher mean tacrolimus levels (14.1 ng/mL, p = 3e-5) compared to other SARS-CoV-2 positive (8.7 ng/mL) and negative/untested (7.9 ng/mL) patients, respectively. Among SARS-CoV-2 patients, those prescribed Paxlovid are more likely to present with supratherapeutic tacrolimus levels (OR 4.1, 95% CI 1.6 – 10.7). A detailed case review of three organ transplant recipients presenting with tacrolimus levels >60 ng/mL and creatinine levels increased by 0.45 ± 0.27 mg/dL from baseline shows Paxlovid was prescribed at outside facilities, and regular tacrolimus dose was continued. Three other patients exhibited supratherapeutic tacrolimus levels (20 – 30 ng/mL), and creatinine levels increased by 0.41 ± 0.23 mg/dL from baseline despite dose reduction or cessation before initiating Paxlovid. Conclusion Our findings highlight the importance of communication between primary and tertiary care providers and caution when prescribing Paxlovid in populations managed with tacrolimus therapy.

Myricetin inhibits CYP3A4, GST, and MRP1 in hepatic cancer cells

AbstractHerbal and nutritional supplements are widely used to prevent and treat many diseases, including cancer. Tumor cells modify metabolic enzyme systems like CYP3A4 and GST. They also overexpress MRP1, an ATP-binding cassette transporter subfamily G (ABCG2) member. Drug efflux may increase, reducing tumor cell drug accumulation and developing drug resistance that leads to significant obstacles in cancer care. Natural products' ability to overcome cancer's multidrug resistance is interesting. Their ability to affect several targets makes them valuable in addressing drug resistance from diverse approaches. The potential of natural flavonoid; Myricetin (MYR) to modulate CYP3A4, GST, and MRP1 activity and expression in hepatic cancer cells was evaluated to prove its targeting and preventing these pathways of multidrug resistance. The cell proliferation of MYR was determined using an MTT assay. Specific enzyme assays, efflux assay, and gene expression using RT-PCR were used to evaluate MYR effect in hepatic cell lines HepG-2 and Huh-7. MYR has a noteworthy cytotoxic effect compared to doxorubicin (DOX) with IC50 > 100 μM in HepG-2 and Huh-7 cells. MYR showed potent inhibition of CYP3A4 and GST enzyme activity and MRP1 efflux function and downregulated their gene expression in a dose-dependent manner in both cells. MYR100 dose was the most significant effective dose. MRY100 decreased CYP3A4 activity by 67.5% (P < 0.05) and 55% (P < 0.01) and downregulated the gene by 0.2-fold (P < 0.001) and 0.3-fold (P < 0.001) in HepG-2 and Hub-7 cells, respectively. After treatment with MRY100, GST activity decreased significantly in both cells, reaching 47.6% (P < 0.001) and 33.2% and GST gene downregulation was 0.12 and 0.21-fold (P < 0.001). MRY100 inhibited MRP1 efflux pump 2.3 times (P < 0.001) and 1.9 times (P < 0.001) more effectively than PC, resulting in a 0.23-fold and 0.12-fold downregulation of MRP1 genes in HepG-2 and Hub-7 cells. The result will validate the use of MYR to interact with the metabolism phases and could be used as adjuvant therapy in cancer prevention and treatment approaches.

7432 Secondary Adrenal Insufficiency Caused By Concurrent Treatment With Budesonide And Itraconazole

Abstract Disclosure: F. Anjum: None. M.G. Jakoby: None. Introduction: Inhaled corticosteroids (ICS) are unlikely to affect corticotroph axis function even at high doses due to low systemic absorption. However, co-treatment with drugs that reduce hepatic clearance of ICS may predispose patients to secondary adrenal insufficiency (AI). We report a case of secondary AI that occurred during concurrent treatment with budesonide and itraconazole. Case presentation: A 42-year-old female with longstanding asthma managed with inhaled budesonide (160 μg twice daily) was started on itraconazole (200 mg twice daily) for management of pulmonary histoplasmosis. Over the next three months, she experienced severe fatigue, and laboratory evaluation was notable for an undetectable (< 0.4 μg/dL) 8 AM cortisol level. Serum sodium (140 mM, 136-145) and potassium (4.6 mM, 3.5-5.1) were unremarkable, and a diagnosis of drug induced secondary AI was made. Treatment with hydrocortisone (15 mg in the morning, 5 mg in the evening) was started, and the patient’s infectious disease specialist stopped itraconazole, substituting posaconazole (300 mg daily) for an additional six months. Her pulmonologist substituted fluticasone (250 μg twice daily) for budesonide. After an approximate two-month hydrocortisone taper, 8 AM ACTH level was easily detectable (37.2 pg/mL, 7.2-63.3), though 30 min stimulated cortisol level was subnormal (11.1 μg/dL, expected > 18). Hydrocortisone was successfully tapered off over an additional two-months (30 min stimulated cortisol 23.4 μg/dL). Discussion: The literature on ICS induced secondary AI is generally case reports and series, and the incidence is very low (1.1/10,000 patient-years at risk). Limited oral bioavailability, high deposition in lungs, extensive protein binding, and robust hepatic clearance are factors that minimize the effects of ICS on corticotroph axis function. However, concurrent treatment with potent CYP3A4 inhibitors like itraconazole can significantly reduce hepatic clearance of ICS and predispose to systemic effects, including Cushing syndrome when high dose ICS are prescribed or secondary AI at lower doses. In a series of 25 cystic fibrosis patients co-treated with itraconazole and budesonide, 11/25 (44%) developed secondary AI. Our patient likely developed secondary AI but not Cushing syndrome due to treatment with low dose budesonide. This case illustrates the importance that endocrinologists recognize CY3A4 inhibiting drugs as a risk factor for secondary AI in patient treated with ICS. Presentation: 6/3/2024

Intercalating compounds alongside DNA helicase Q1 Plasmodium falciparum 3D7: Assessments of the Pharmacokinetic Properties Prediction of ADME.

Quantum chemical & molecular docking practices to deliver new perceptions into how etoposide, novobiocin, nogalamycin and netropsin interact with the biological targets PF3D7_0918600 (Plasmodium falciparum 3D7). Further the pharmacokinetics of a drug candidate which influenced by a variety of factors, including P- glycoprotein (Pgp) transport, PBB (Plasma protein binding), & BBB (Blood-brain barrier) permeation help to forecast the pharmacological characteristics of acetyl-CoA reductase inhibitors (ADMEs) and their metabolites. At this point, we have elevated four compounds such as etoposide, novobiocin, nogalamycin & netropsin. We have also studied molecular docking against the target protein of the Plasmodium falciparum (PF3D7_0918600) through exhausting the AutoDock Vina platform and AutoDock-Tools (ADT) and pharmacokinetic properties were carried out using the ADMET 2.0. The relative results of molecular docking recommended a greater binding affinity of novobiocin with the selected receptors among other compounds. In-silico ADME screening is a computational approach utilised to forecast the pharmacological characteristics of acetyl- CoA reductase inhibitors (ADMEs) and their metabolites. The ADMEs are based on the adsorption-desorption kinetics and pharmacopoeia. Adsorption and distribution analysis are used to assess the potential of the drug candidate. In vitro ADME is exploited to expect the effect of Pgp transport on the drug candidates. ADME has been used to predict CYP1A2 inhibitors and to predict PPB and BBB penetration. This paper summarizes the current knowledge on molecular docking, ADME and identifies potential drug candidates for ADME in vitro and in vivo.

Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the invivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

Probe substrates assay estimates the effect of polyphyllin H on the activity of cytochrome P450 enzymes in human liver microsomes.

Cytochrome P450 enzymes (CYPs) play a crucial role in phase I metabolic reactions. The activity of CYPs would affect therapeutic efficacy and may even induce toxicity. Given the complex components of traditional Chinese medicine, it is important to understand the effect of active ingredients on CYPs activity to guide their prescription. This study aimed to evaluate the effect of polyphyllin H on the activity of CYPs major isoforms providing a reference for the clinical prescription of polyphyllin H and its source herbs. The effects of polyphyllin H were evaluated in pooled human liver microsomes using probe substrates of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 to determine their activities. The Lineweaver-Burk was used to model the inhibition, and a time-dependent inhibition experiment was performed to understand the characteristics of the inhibition. Polyphyllin H significantly suppressed the activity of CYP1A2, 2D6, and 3A4 with IC50 values of 6.44, 13.88, and 4.52 μM, respectively. The inhibition of CYP1A2 and 2D6 was best fitted with a competitive model, yielding the inhibition constant (Ki) values of 3.18 and 6.77 μM, respectively. The inhibition of CYP3A4 was fitted with the non-competitive model with the Ki value of 2.38 μM. Moreover, the inhibition of CYP3A4 was revealed to be time-dependent with the inhibition parameters inhibition constant (KI) and inactivation rate constant (Kinact) values of 2.26 μM-1 and 0.045 min-1. Polyphyllin H acted as a competitive inhibitor of CYP1A2 and 2D6 and a non-competitive and time-dependent inhibitor of CYP3A4.

Kinetics of the inhibition of CYP3A4 and CYP2C19 activity by jabara juice and identification of the responsible inhibitory components

Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6′,7′-dihydroxybergamottin, and to identify the inhibitory compound(s).CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed.The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (KI) of 10.0 and 7.90 µM and maximal inactivation rate constants (kinact,max) of 0.00856 and 0.0134 min−1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

Effect of CYP3A5*3 genotype on exposure and efficacy of quetiapine: A retrospective, cohort study

BackgroundThe involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. MethodsPatient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. ResultBased on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype.The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and dealkylated quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 <0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. ConclusionThe results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to carefully monitor and potentially adjust the dosage for patients with this genotype to avoid adverse effects. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes. This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [Emax], Emax, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment. The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid Emax model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin. These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.