Structural perspectives of the CYP3A family and their small molecule modulators in drug metabolism

Wright, William C.; Chenge, Jude; Chen, Taosheng

doi:10.1016/j.livres.2019.08.001

Cited by 29 publications

(19 citation statements)

References 140 publications

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“…However, the absence of increase in the hematologic toxicities is reassuring and suggests no relevant consequences on cyclophosphamide metabolism when combined with tazemetostat. Furthermore, vincristine is a CYP3A substrate, with a nonactive primary metabolite, and tazemetostat is a weak CYP3A inducer (30), suggesting that vincristine drug exposure should not be increased with the association.…”

Section: Discussionmentioning

confidence: 99%

A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features

Sarkozy

Morschhauser

Dubois³

et al. 2020

Clinical Cancer Research

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The histone-methyl transferase EZH2, catalytic subunit of the PRC2 complex involved in transcriptional regulation, is mutated in approximately 25% of germinal center B-cell lymphomas. Aberrant proliferative dependency on EZH2 activity can be targeted by the orally available EZH2 inhibitor tazemetostat (EPZ-6438). We report the results of the phase Ib tazemetostat plus R-CHOP combination (NCT02889523), in patients 60 to 80 years of age with newly diagnosed diffuse large B-cell lymphoma.Patients and Methods: The primary objective of this doseescalation study was to evaluate the safety of the combination and to determine the recommended phase II dose (RP2D) of tazemetostat.Results: A total of 17 patients were enrolled. During C1 and C2, two dose-limiting toxicities were observed: one grade 3 constipation at 400 mg and one grade 5 pulmonary infection at 800 mg. Grade 3 or more toxicities observed in more than 10% of the patients were constipation (24%), nausea (12%), and hypokalemia (12%). Grade 3 to 4 hematologic adverse events were recorded in 8 patients (47%): neutropenia (47%), leukopenia (29%), anemia (18%), and thrombocytopenia (12%). The tazemetostat RP2D was 800 mg. No organ-oriented toxicity increased with tazemetostat dosage escalation (severity and incidence). At 800 mg, AUC and C max of tazemetostat were similar compared with the single-agent study (E7438-G000-101).Conclusions: The RP2D of tazemetostat combined with R-CHOP is 800 mg twice a day. The association presents safety and PK comparable with R-CHOP alone. Preliminary efficacy data are encouraging and further investigations in phase II trial are warranted.

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Section: Discussionmentioning

confidence: 99%

A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features

Sarkozy

Morschhauser

Dubois³

et al. 2020

Clinical Cancer Research

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“…The cytochrome P450 (CYP)3A members are the most abundant CYP enzymes in the human small intestine and liver and are particularly important in drug metabolism and elimination [ 3 , 4 ]. P-glycoprotein (P-gp), an efflux membrane transporter expressed on the apical membrane of epithelial cells in various tissues, including the enterocyte brush border and liver, is one of the important membrane transporters in drug elimination.…”

Section: Introductionmentioning

confidence: 99%

“…1 Values were expressed as the means of duplicate data 2. Total catechins: EGC + EGCG + EC + GCG + ECG 3. Total sugars: Glucose + Sucrose + Fructose.…”

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confidence: 99%

Beverage–Drug Interaction: Effects of Green Tea Beverage Consumption on Atorvastatin Metabolism and Membrane Transporters in the Small Intestine and Liver of Rats

Yao

Hsu

2020

Membranes

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Green tea (GT) beverages are popular worldwide and may prevent the development of many chronic diseases including cardiovascular disease and cancer. To investigate whether the consumption of a GT beverage causes drug interactions, the effects of GT beverage consumption on atorvastatin metabolism and membrane transporters were evaluated. Male rats were fed a chow diet with tap water or the GT beverage for 3 weeks. Then, the rats were given a single oral dose (10 mg/kg body weight (BW)) of atorvastatin (ATV), and blood was collected at various time points within 6 h. The results show that GT consumption increased the plasma concentrations (AUC0–6h) of ATV (+85%) and 2-OH ATV (+93.3%). GT also increased the 2-OH ATV (+40.9%) and 4-OH ATV (+131.6%) contents in the liver. Decreased cytochrome P450 (CYP) 3A enzyme activity, with no change in P-glycoprotein expression in the intestine, was observed in rats treated with GT. Additionally, GT increased hepatic CYP3A-mediated ATV metabolism and decreased organic anion transporting polypeptides (OATP) 2 membrane protein expression. There was no significant difference in the membrane protein expression of OATP2B1 and P-glycoprotein in the intestine and liver after the GT treatment. The results show that GT consumption may lower hepatic OATP2 and, thus, limit hepatic drug uptake and increase plasma exposure to ATV and 2-OH ATV.

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“…Studies have shown that phenylalanine could inhibit the activity of adenosine triphosphate (ATP) diphosphate hydrolase, thereby increasing the amount of ATP (Berti et al, 2002). The transport activity of P-gp, which plays an important role in drug excretion (Wright et al, 2019), requires the involvement of ATP (Schinkel & Jonker, 2012).…”

Section: Discussionmentioning

confidence: 99%

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor

Zhang

Sun

Wei

et al. 2021

Biomedical Chromatography

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Ticagrelor is a first-line clinical drug for the treatment of acute coronary syndrome, but its oral bioavailability is relatively low. Flavonoids (polyphenol compounds commonly found in plant foods) seriously affect human metabolism and health. This study compared the effects of quercetin, luteolin and catechin on the pharmacokinetic parameters of ticagrelor and found that quercetin can significantly increase the C max and area under the curve from time zero to 36 h (AUC 0-36 ) of ticagrelor, that is, quercetin can enhance the bioavailability of ticagrelor, but luteolin and catechin cannot.The difference between the ticagrelor group and the combination of quercetin and ticagrelor was analyzed through untargeted metabolomics methods and multivariate data analysis, which identified changes in the levels of seven metabolites (deoxycholic acid, taurocholic acid, glycocholic acid, glycoursodeoxycholic acid, tryptophan, phenylalanine and kynurenine). Based on the changes of these metabolites, we found that the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids were changed. A metabolomics study revealed that quercetin improves the oral bioavailability of ticagrelor and that this might rely on changing the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids. The research results at the metabolic level provide us with a strong basis and direction for further exploring the mechanism underlying quercetin's ability to enhance the bioavailability of ticagrelor, and this may be useful for finding new agents that enhance the bioavailability.

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Structural perspectives of the CYP3A family and their small molecule modulators in drug metabolism

Cited by 29 publications

References 140 publications

A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features

A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features

Beverage–Drug Interaction: Effects of Green Tea Beverage Consumption on Atorvastatin Metabolism and Membrane Transporters in the Small Intestine and Liver of Rats

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor

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