Consequences of a Chronic Exposure of Cultured Brain Astrocytes to the Anti-Retroviral Drug Efavirenz and its Primary Metabolite 8-Hydroxy Efavirenz

Arend, Christian; Rother, Alica; Stolte, Stefan; Dringen, Ralf

doi:10.1007/s11064-016-2059-x

Cited by 11 publications

(4 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The trifluoromethyl (CF 3 ) group functions as an excellent bioisostere of the methyl group in medicinal chemistry, owing to its potential to improve the metabolic stability, bioavailability, and cellular membrane permeability of molecules . Accordingly, incorporation of a trifluoromethyl group into molecular skeletons has attracted significant interest for organic synthesis. − Allenol is a versatile synthon that undergoes diverse transformations, including eliminations, substitutions, and rearrangements (Figure A) .…”

mentioning

confidence: 99%

Synthesis of Trifluoromethyl-Substituted Allenols via Catalytic Trifluoromethylbenzoxylation of 1,3-Enynes

Yang

Shi

et al. 2023

ACS Catal.

View full text Add to dashboard Cite

Allenol has been identified as a versatile building block for organic synthesis, and numerous efforts have been made to synthesize and apply allenol. However, limited efforts have been made to obtain a trifluoromethyl-substituted allenol. Here, by using a readily available 1,3-enyne as the starting material, a coppercatalyzed trifluoromethylbenzoxylation process was developed for efficient synthesis of trifluoromethyl-substituted allenols using Togni-II reagent as the reaction partner. Triple roles of the Togni-II reagent, including as the source of the trifluoromethyl group, as the source of the hydroxyl group, and as the oxidant, were elucidated in this transformation. Moreover, late-stage diversification was performed, which revealed the application potential of trifluoromethyl-substituted allenols for the preparation of various trifluoromethyl-substituted compounds.

show abstract

mentioning

confidence: 99%

Synthesis of Trifluoromethyl-Substituted Allenols via Catalytic Trifluoromethylbenzoxylation of 1,3-Enynes

Yang

Shi

et al. 2023

ACS Catal.

View full text Add to dashboard Cite

show abstract

“…of recent reports in part incriminated 8OHEFV in the neurotoxic adverse reactions associated with efavirenz administration, emphasizing the need to characterize the time course of both EFV and 8OHEFV in the body (7,9).…”

mentioning

confidence: 99%

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Habtewold

Aklillu

Makonnen

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 Ϯ 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C¡T, 3842A¡G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (K a ) and absorption lag time (A lag ) (K a ϭ 0.2 h Ϫ1 ; A lag ϭ 0.83 h; central compartment clearance [CL c /F] for CYP2B6*1/*1 ϭ 18 liters/h, for CYP2B6*1/*6 ϭ 14 liters/h, and for CYP2B6*6/*6 ϭ 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL p /F ϭ 32 liters/h), followed by capacity-limited return (V max ϭ 4,400 ng/ml/h; K m ϭ 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.KEYWORDS efavirenz, 8-hydroxy-efavirenz, peripheral blood mononuclear cells, population pharmacokinetics E favirenz (EFV)-based antiretroviral therapy remains the preferred first-line treatment option in important international guidelines, including those of the World Health Organization (1). EFV displays a wide between-patient pharmacokinetic (PK) variability (2, 3). This is ascribed partially to genetic variation of the CYP2B6 enzyme, which is primarily responsible for the metabolism of efavirenz to 8-hydroxy-efavirenz (8OHEFV) (4, 5). Efavirenz is described to have a narrow safety margin (6-8). In addition, a couple

show abstract

“…Of interest, the HIV-protease inhibitor ritonavir potently reduces glucose transporter-1 activity and glycolysis (87) (Figure 1, Table 2). In contrast, the HIV-reverse transcriptase inhibitors efavirenz or zidovudine stimulates glycolysis and increases lactate levels (106,110) (Figure 1, Table 3).…”

Section: Impact Of the Hiv-protease Inhibitors Or Hiv-reverse Transcriptase Inhibitors On The Sequential Phases Of Angiogenesismentioning

confidence: 99%

The Anti-Angiogenic Effects of Anti-Human Immunodeficiency Virus Drugs

Barillari

2020

Front. Oncol.

View full text Add to dashboard Cite

The growth and metastasis of malignant tumors benefit from the formation of blood vessels within the tumor area. There, new vessels originate from angiogenesis (the sprouting of pre-existing neighboring vessels) and/or vasculogenesis (the mobilization of bone marrow-derived endothelial cell precursors which incorporate in tumor vasculature and then differentiate into mature endothelial cells). These events are induced by soluble molecules (the angiogenic factors) and modulated by endothelial cell interactions with the perivascular matrix. Given angiogenesis/vasculogenesis relevance to tumor progression, anti-angiogenic drugs are often employed to buttress surgery, chemotherapy or radiation therapy in the treatment of a wide variety of cancers. Most of the anti-angiogenic drugs have been developed to functionally impair the angiogenic vascular endothelial growth factor: however, this leaves other angiogenic factors unaffected, hence leading to drug resistance and escape. Other anti-angiogenic strategies have exploited classical inhibitors of enzymes remodeling the perivascular matrix. Disappointingly, these inhibitors have been found toxic and/or ineffective in clinical trials, even though they block angiogenesis in pre-clinical models. These findings are stimulating the identification of other anti-angiogenic compounds. In this regard, it is noteworthy that drugs utilized for a long time to counteract human immune deficiency virus (HIV) can directly and effectively hamper molecular pathways leading to blood vessel formation. In this review the mechanisms leading to angiogenesis and vasculogenesis, and their susceptibility to anti-HIV drugs will be discussed.

show abstract

Consequences of a Chronic Exposure of Cultured Brain Astrocytes to the Anti-Retroviral Drug Efavirenz and its Primary Metabolite 8-Hydroxy Efavirenz

Cited by 11 publications

References 40 publications

Synthesis of Trifluoromethyl-Substituted Allenols via Catalytic Trifluoromethylbenzoxylation of 1,3-Enynes

Synthesis of Trifluoromethyl-Substituted Allenols via Catalytic Trifluoromethylbenzoxylation of 1,3-Enynes

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

The Anti-Angiogenic Effects of Anti-Human Immunodeficiency Virus Drugs

Contact Info

Product

Resources

About