cytochrome p450 3A4

Human cytochrome P450 3A4 (CYP3A4) is a drug-metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human-like regulation of the coding genes. A normal diet (ND, CE-2), CE-2 with 1% cholesterol and 0...

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively)...

Autoinduction of cytochrome P450 (P450) 3A4-mediated metabolism of thalidomide was investigated in humanized-liver mice and human hepatocyte-derived HepaSH cells. The mean plasma ratios of 5-hydroxythalidomide and glutathione adducts to thalidomide were significantly induced (3.5- and 6.0-fold, respectively) by thalidomide treatment daily at 1000 mg/kg for 3 days and measured at 2 h after the fourth administration (on day 4). 5-Hydroxythalidomide was metabolically activated by P450 3A4 in HepaSH cells pretreated with 300 and 1000 μM thalidomide, and 5,6-dihydroxythalidomide was detected...

Cytochrome P450 enzymes are a superfamily of enzymes responsible for the metabolism of a variety of medicines and xenobiotics. Among the Cytochrome P450 family, five isozymes that include 1A2, 2C9, 2C19, 2D6, and 3A4 are most important for the metabolism of xenobiotics. Inhibition of any of these five CYP isozymes causes drug-drug interactions with high pharmacological and toxicological effects. So, the inhibition or non-inhibition prediction of these isozymes is of great importance. Many techniques based on machine learning and deep learning algorithms are currently being used to predict whether these isozymes will be inhibited or not...

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748)...

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme and is commonly used as a pharmacokinetic (PK) enhancer in antiviral therapies because it increases bioavailability of concomitantly administered antivirals. Decades of experience with ritonavir-enhanced HIV therapies and, more recently, COVID-19 therapies demonstrate that boosting doses of ritonavir are well tolerated, with an established safety profile. The mechanisms of PK enhancement by ritonavir result in the potential for drug-drug interactions (DDIs) with several classes of drugs, thus making co-medication management an important consideration with enhanced antiviral therapies...

A growing body of literature has linked early-life exposures to polycyclic aromatic hydrocarbons (PAH) with adverse neurodevelopmental effects. Once in the body, metabolism serves as a powerful mediator of PAH toxicity by bioactivating and detoxifying PAH metabolites. Since enzyme expression and activity vary considerably throughout human development, we evaluated infant metabolism of PAHs as a potential contributing factor to PAH susceptibility. We measured and compared rates of phenanthrene and retene (two primary PAH constituents of woodsmoke) metabolism in human hepatic microsomes from individuals ≤21 months of age to a pooled sample ( n = 200) consisting primarily of adults...

BACKGROUND AND OBJECTIVE: Viloxazine extended-release (ER) [Qelbree® ] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. METHODS: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0...

Cytochrome P450 3A4 (CYP3A4) is one of the most important drug-metabolizing enzymes in the human body and is well known for its complicated, atypical kinetic characteristics. The existence of multiple ligand-binding sites in CYP3A4 has been widely recognized as being capable of interfering with the active pocket through allosteric effects. The identification of ligand-binding sites other than the canonical active site above the heme is especially important for understanding the atypical kinetic characteristics of CYP3A4 and the intriguing association between the ligand and the receptor...

Total saikosaponins (TSS) form a group of chemically and biologically active components that can be extracted from Bupleurum, with reported antidepressive, anti-inflammatory, antiviral, antiendotoxin, antitumor, anti-pulmonary fibrosis and anti-gastric ulcer effects. Bupleurum or TSS is frequently utilized in clinical practice alongside other medications (such as entecavir, lamivudine, compound paracetamol and amantadine hydrochloride capsules), leading to an increased risk of drug-drug interactions. The cytochrome P450 (CYP) family serves a critical role in the metabolism of numerous essential drugs (such as tamoxifen, ibuprofen and phenytoin), where the majority of drug interactions involve CYP-mediated metabolism...

The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in significant differences in treatment efficacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models...

Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations...

Flavonoids, a diverse group of polyphenolic compounds found abundantly in fruits, vegetables, and beverages like tea and wine, offer a plethora of health benefits. However, they have a potential interaction with drug metabolism, particularly through the inhibition of the cytochrome P450 3A4 enzyme, the most versatile and abundant enzyme in the liver. CYP3A4 is responsible for metabolizing approximately 50% of clinically prescribed drugs across diverse therapeutic classes, so these interactions have raised concerns about potential adverse effects...

OBJECTIVE: Due to the high clinical heterogeneity of epilepsy, there is a critical need for novel metrics aimed at capturing its biological and phenotypic complexity. Frailty is increasingly recognized in various medical disciplines as a useful construct to understand differences in susceptibility to adverse outcomes. Here, we develop a frailty index (FI) for patients with epilepsy (PwE) and explore its association with demographic and clinical features. METHODS: In this cross-sectional study, we consecutively enrolled 153 PwE from an outpatient epilepsy clinic...

This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4β-hydroxycholesterol (4β-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL)...

Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas...

Data are presented on the formation of potentially toxic metabolites of drugs that are substrates of human drug metabolizing enzymes. The tabular data lists the formation of potentially toxic/reactive products. The data were obtained from in vitro experiments and showed that the oxidative reactions predominate (with 96% of the total potential toxication reactions). Reductive reactions (e.g., reduction of nitro to amino group and reductive dehalogenation) participate to the extent of 4%. Of the enzymes, cytochrome P450 (P450, CYP) enzymes catalyzed 72% of the reactions, myeloperoxidase (MPO) 7%, flavin-containing monooxygenase (FMO) 3%, aldehyde oxidase (AOX) 4%, sulfotransferase (SULT) 5%, and a group of minor participating enzymes to the extent of 9%...

STUDY AIM: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone. METHODS: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1...

The Cytochrome P450 (CYP) enzymes metabolize a variety of drugs, which may potentially lead to toxicity or reduced efficacy when drugs are co-administered. These drug-drug interactions are often manifested by CYP3A4, the most prevalent of all CYP isozymes. We carried out multiple MD simulations employing CAVER to quantify the channels, and Hidden Markov Models (HMM) to characterize the behavior of the gating residues. We discuss channel properties, bottleneck residues with respect to their likelihood to deem the respective channel ingress or egress, gating residues regarding their open or closed states, and channel location relative to the membrane...

BACKGROUND AND OBJECTIVES: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin...