Efavirenz (formerly L-743,726/DMP-266) targets human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) with an IC50 of 1.7 nM (enzyme activity inhibition) and an EC50 of 3.0 nM (anti-HIV-1 activity in cell culture)[1]

研究发现依非韦伦 (L-743726) 可以抑制一组对表达单一 RT 氨基酸取代的非核苷类逆转录酶抑制剂 (NNRTI) 具有抗性的突变病毒，95% 抑制剂量≤ 1.5μM。当检查依非韦伦抑制不同聚合酶的能力时，发现它缺乏活性（IC50>300μM）。依非韦伦可有效抑制多种野生型 T 淋巴细胞系适应性变异。在原代淋巴样细胞和单核细胞样细胞培养物中，病毒的野生型原代分离株表现出相同的活性（IC95，1.5 至 3.0 nM）。此外，含有 RT 氨基酸变化（赋予对其他 NNRTI 耐药性）的 HIV-1 基因型可被依非韦伦有效抑制。出于比较目的[1]。 efavirenz 是一种非核苷类似物逆转录酶抑制剂 (NNRTI)，IC50 为 60 nM[2]。 efavirenz 的 IC50 为 17 nM，利用 RNA PPT 引发的底物抑制合成[3]。

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依法韦仑（Efavirenz） 浓度依赖性强效抑制纯化的重组HIV-1 RT活性，1.7 nM时抑制率达50%，8.0 nM时抑制率达90%[1]
- 在感染HIV-1（IIIB株）的MT-4淋巴母细胞中，依法韦仑（Efavirenz） 抑制病毒复制的EC50为3.0 nM，治疗指数（CC50/EC50）大于3333（CC50>10 μM，即引起50%细胞毒性的浓度）[1]
- 该化合物与齐多夫定（AZT）等核苷类逆转录酶抑制剂（NRTIs）无交叉耐药性，对AZT耐药的HIV-1毒株仍有抑制作用，EC50为3.2 nM[1]
- 依法韦仑（Efavirenz） 结合于HIV-1 RT的非核苷结合口袋，诱导酶的构象改变，从而阻断其逆转录活性[1]

依非韦伦 (Efavirenz) (L-743726) 静脉注射后会很快从大鼠体内消除，但从猴子体内消除的速度要慢得多。在这两个物种中，大体积的分布（身体含水量的两到四倍）表明广泛的组织结合。大鼠口服生物利用度为 16%。静脉注射1mg/kg依非韦伦后，在猴子体内的半衰期超过2.5小时。口服依非韦伦吸收良好。当给猴子口服 0.5% 甲基纤维素水溶液的细悬浮液时，血浆水平始终很高。 2.0 mg/kg 剂量后约 3.0 小时，达到 0.5μM 的峰值水平。据测算，绝对生物利用度为42%。剂量为 10 mg/kg 时，血浆峰浓度为 3.22 μM。一只黑猩猩口服剂量为 10 mg/kg，给药后 2、8 和 24 小时血浆浓度分别为 4.12、2.95 和 2.69 μM[1]。

HIV-1 RT活性抑制实验：将系列浓度的依法韦仑（Efavirenz） 与纯化的重组HIV-1 RT、模板-引物复合物（poly(rC)-oligo(dG)）及[³H]-标记的脱氧鸟苷三磷酸（[³H]-dGTP）在反应缓冲液中37°C孵育60分钟。加入三氯乙酸（TCA）终止反应，通过液体闪烁计数器检测沉淀的放射性（即掺入的[³H]-dGTP量），相对于溶媒对照组计算抑制率，采用非线性回归分析确定IC50值[1]

抗HIV-1细胞培养实验：MT-4细胞以每孔2×10⁴个细胞的密度接种于96孔板，用HIV-1（IIIB株）以感染复数（MOI）0.01感染细胞。感染后立即加入系列浓度（0.1–1000 nM）的依法韦仑（Efavirenz），在37°C、5% CO₂培养箱中培养5天。通过显微镜观察细胞病变效应（CPE）评估病毒复制，计算抑制50% CPE的浓度（EC50）；在未感染HIV-1的MT-4细胞中检测相同浓度化合物的细胞毒性，确定CC50（50%细胞毒性浓度），并计算治疗指数（CC50/EC50）[1]
- AZT耐药HIV-1抑制实验：采用上述相同细胞培养方案，以AZT耐药HIV-1毒株（A01A株）感染细胞，依法韦仑（Efavirenz） 浓度调整为0.1–1000 nM，通过CPE抑制法确定EC50[1]

Formulated in 0.5% methocel(oral); DMSO(i.v.); 10, 40, and 160 mg/kg(oral); 2, 5, 10, 15 mg/kg(i.v.); i.v. or p.o. administration
Sprague-Dawley rats

Absorption, Distribution and Excretion
Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.
Oral bioavailability of efavirenz may be affected by administration with food. Administration of a single 600-mg dose of efavirenz as capsules with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% of calories from fat) or a reduced-fat, normal-calorie meal (440 kcal, 2 g fat, 4% of calories from fat) increases peak plasma concentrations of the drug by 39 or 51%, respectively, and AUC by 22 or 17%, respectively, compared with administration in the fasting state. Administration of a single 600-mg dose of efavirenz as tablets with a high-fat, high-calorie meal (approximately 1000 kcal, 500-600 kcal from fat) increases peak plasma concentrations and AUC of the drug by 79 and 28%, respectively, compared with administration in the fasting state.
Efavirenz is excreted principally in the feces, both as unchanged drug and metabolites. Excretion of efavirenz has been evaluated in individuals receiving 400 mg daily for 1 month. Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (less than 1% as unchanged drug), and 16-61% was excreted in feces (predominantly as unchanged drug).
Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin.
In HIV-infected adults receiving efavirenz 200, 400, or 600 mg once daily, peak plasma concentrations of the drug generally occur in 3-5 hours and steady-state plasma concentrations are achieved in 6-10 days. Following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance of the drug. In one study in individuals receiving efavirenz 200-400 mg once daily for 10 days, plasma concentrations of the drug were 22-42% lower than those predicted from single-dose studies. Following oral administration of efavirenz 600 mg once daily in HIV-infected adults, peak plasma concentration, trough plasma concentration, and AUC of the drug at steady-state averaged 4.1 mcg/mL, 1.8 mcg/mL, and 58. mcg*hour/mL, respectively.
For more Absorption, Distribution and Excretion (Complete) data for EFAVIRENZ (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1.
Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming the N-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9.
Efavirenz is a substrate for cytochrome p450 isoforms, particularly CYP3A4 and CYP2B6. The 8-hydroxy metabolite is excreted in the urine, and the glucuronide conjugate of 8-hydroxy-efavirenz is present in plasma and urine. Sixty percent of the dose is excreted in urine as the glucuronide conjugate.
Efavirenz has known human metabolites that include 8-hydroxyefavirenz.

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Biological Half-Life
40-55 hours
The terminal elimination half-life of efavirenz is prolonged in patients with chronic liver disease. Following oral administration of a single 400-mg dose of efavirenz, an elimination half-life of 152 or 118 hours was reported in individuals with or without chronic liver disease, respectively.
The terminal elimination half-life of efavirenz reported in single-dose studies is longer than that reported in multiple-dose studies and has averaged 52-76 hours after a single oral dose and 40-55 hours following administration of 200-400 mg daily for 10 days.

Interactions
Alcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS. This pharmacokinetics study (n?=?40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction. EFV administration was associated with decreased S-Methyl-N-N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS (p?=?.001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied.
Administration of efavirenz in patients receiving psychoactive drugs may result in increased CNS effects.
Efavirenz may decrease the plasma concentrations of amprenavir; no specific dosage adjustment can be recommended until additional studies are conducted.
Efavirenz may inhibit the metabolism of these medications /astemizole or cisapride/ through competition for the CYP3A4 isoenzyme, which may increase the potential for cardiac arrhythmias; use is contraindicated.
For more Interactions (Complete) data for EFAVIRENZ (15 total), please visit the HSDB record page.

[1]. L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1995 Dec;39(12):2602-5.

[2]. Differential susceptibility of HIV-1 reverse transcriptase to inhibition by RNA aptamers in enzymatic reactions monitoring specific steps during genome replication. J Biol Chem. 2006 Sep 1;281(35):25712-22.

[3]. HIV-1 reverse transcriptase plus-strand initiation exhibits preferential sensitivity to non-nucleoside reverse transcriptase inhibitors in vitro. J Biol Chem. 2007 Mar 16;282(11):8005-10.

Therapeutic Uses
Anti-HIV Agents; Reverse Transcriptase Inhibitors
Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>/= 3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.
Efavirenz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. /Included in US product labeling/

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Drug Warnings
To report a case of acquired long QT syndrome that, after exclusion of all other possible causes, was probably related to therapy with efavirenz, a novel nonnucleoside reverse transcriptase inhibitor.
About 53% of adults receiving efavirenz (600 mg once daily) in controlled clinical studies reported adverse CNS effects such as abnormal dreams, abnormal thinking, agitation, amnesia, confusion, depersonalization, dizziness, euphoria, hallucinations, impaired concentration, insomnia, somnolence, and stupor; these adverse effects were reported in 25% of adults in the control groups not receiving efavirenz. These effects were described as mild (do not interfere with daily activities) in 33.3%, moderate (may interfere with daily activities) in 17.4%, or severe (interrupt usual daily activities) in 2% of patients receiving efavirenz and required discontinuance of the drug in 2.1%. Dizziness was reported in 28.1% and insomnia was reported in 16.3% of patients receiving the drug. Impaired concentration, somnolence, or abnormal dreams were reported in 6.2-8.3% and hallucinations were reported in 1.2% of patients.
Serious adverse psychiatric symptoms have been reported rarely in adults receiving efavirenz. Severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, or manic reactions have been reported in 0.4-1.6% of patients receiving efavirenz in controlled clinical studies; these psychiatric symptoms were reported in up to 0.6% of those in the control groups not receiving the drug. The incidence of each of these psychiatric symptoms ranges from 0.3% (for manic reactions) to 2% (for severe depression or suicidal ideation) in patients with a prior history of psychiatric disorders, and these individuals appear to be at greater risk of such symptoms than other individuals. Other psychiatric symptoms reported in controlled clinical studies in adults receiving efavirenz include depression (15.8%), anxiety (11.1%), and nervousness (6.3%); these symptoms were reported in 13.1, 7.6, or 2%, respectively, of those in the control groups not receiving the drug. Although a causal relationship with efavirenz has not been established, there have been occasional postmarketing reports of death by suicide, delusions, or psychosis-like behavior in patients receiving efavirenz. In addition, aggressive reactions, agitation, emotional lability, mania, neurosis,and paranoia have been reported during postmarketing surveillance. There is no evidence that patients who develop adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, abnormal dreams) during efavirenz therapy are at greater risk of developing psychiatric symptoms.
Fatigue has been reported in up to 7% of adults receiving efavirenz in clinical studies. Other adverse nervous system effects reported during postmarketing surveillance include abnormal coordination, ataxia, seizures, hypoesthesia, paresthesia, neuropathy, and tremor. Adverse CNS effects occurred in 18% of children receiving efavirenz in clinical studies.
For more Drug Warnings (Complete) data for EFAVIRENZ (21 total), please visit the HSDB record page.

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Pharmacodynamics
Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.

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Efavirenz (code name L-743,726/DMP-266) is a novel, highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection[1]
- Its mechanism of action involves binding to the non-nucleoside binding pocket of HIV-1 RT, which induces a structural change in the enzyme and blocks its ability to catalyze reverse transcription of viral RNA into cDNA[1]
- The compound exhibits high selectivity for HIV-1 RT over human cellular DNA polymerases (α, β, γ), with IC50 values greater than 10 μM, minimizing potential cytotoxicity to host cells[1]

C14H9CLF3NO2

315.67

315.027

154598-52-4

(Rac)-Efavirenz-d4;1246812-58-7;Efavirenz-d5;1132642-95-5;Efavirenz-13C6;1261394-62-0

64139

White to off-white solid powder

1.5±0.1 g/cm3

422.7±55.0 °C at 760 mmHg

139-141ºC

209.4±31.5 °C

0.0±1.1 mmHg at 25°C

1.582

3.72

38.33

1

5

1

21

519

1

C1CC1C#C[C@]2(C3=C(C=CC(=C3)Cl)NC(=O)O2)C(F)(F)F

XPOQHMRABVBWPR-ZDUSSCGKSA-N

InChI=1S/C14H9ClF3NO2/c15-9-3-4-11-10(7-9)13(14(16,17)18,21-12(20)19-11)6-5-8-1-2-8/h3-4,7-8H,1-2H2,(H,19,20)/t13-/m0/s1

(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one

DMP-266, DMP 266; Efavirenz; Sustiva; Stocrin; DMP-266; DMP 266; trade name: efavirenz; L-743,726; L-743726; DMP266; EFV; L 743726

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (6.59 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (6.59 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (6.59 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。