Delavirdine
(Synonyms: 地拉韦啶; U 90152; BHAP-U 90152) 目录号 : GC35835
A non-nucleoside reverse transcriptase inhibitor
Cas No.:136817-59-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Delavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that selectively inhibits HIV-1 reverse transcriptase over DNA polymerase α and δ in vitro (IC50s = 0.26, 440, and >550 μM, respectively).1 It inhibits growth of clinical isolates of HIV-1 (ED50s = <0.005-0.69 μM). Delavirdine blocks replication of 25 primary HIV-1 isolates, including strains resistant to 3'-azido-2',3'-deoxythymidine (AZT) or 2',3'-dideoxyinosine, with a mean ED50 value of 0.066 μM. Delavirdine also inhibits growth of L. infantum promastigotes (IC50 = 26.1 μM).2 Formulations containing delavirdine have been used in the treatment of HIV.
1.Dueweke, T.J., Poppe, S.M., Romero, D.L., et al.U-90152, a potent inhibitor of human immunodeficiency virus type 1 replicationAntimicrob. Agents Chemother.37(5)1127-1131(1993) 2.Costa, S., Machado, M., Cavadas, C., et al.Antileishmanial activity of antiretroviral drugs combined with miltefosineParasitol Res.115(10)3881-3887(2016)
| Cas No. | 136817-59-9 | SDF | |
| 别名 | 地拉韦啶; U 90152; BHAP-U 90152 | ||
| Canonical SMILES | O=S(NC1=CC=C(NC(C(N2CCN(C3=C(NC(C)C)C=CC=N3)CC2)=O)=C4)C4=C1)(C)=O | ||
| 分子式 | C22H28N6O3S | 分子量 | 456.56 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1903 mL | 10.9515 mL | 21.9029 mL |
| 5 mM | 0.4381 mL | 2.1903 mL | 4.3806 mL |
| 10 mM | 0.219 mL | 1.0951 mL | 2.1903 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Delavirdine: clinical pharmacokinetics and drug interactions
Clin Pharmacokinet 2001;40(3):207-26.PMID:11327199DOI:10.2165/00003088-200140030-00005.
Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 reverse transcriptase. The approved therapeutic regimen for Delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of Delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between Delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; Delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since Delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of Delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of Delavirdine by at least 1 hour. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining Delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of Delavirdine to enhance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining Delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore, the superior virological response observed in antiretroviral regimens containing Delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising Delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction profile of Delavirdine.
Delavirdine: a review of its use in HIV infection
Drugs 2000 Dec;60(6):1411-44.PMID:11152019DOI:10.2165/00003495-200060060-00013.
Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with Delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (Delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that Delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens. Since Delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1,000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups. Conclusions: In combination with NRTIs. Delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of Delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since Delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.
Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4
Curr Drug Metab 2008 May;9(4):310-22.PMID:18473749DOI:10.2174/138920008784220664.
Human cytochrome P450 (CYP) 3A4 is the most abundant hepatic and intestinal phase I enzyme that metabolizes approximately 50% marketed drugs. The crystal structure of bound and unbound CYP3A4 has been recently constructed, and a small active site and a peripheral binding site are identified. A recent study indicates that CYP3A4 undergoes dramatic conformational changes upon binding to ketoconazole or erythromycin with a differential but substantial (>80%) increase in the active site volume, providing a structural basis for ligand promiscuity of CYP3A4. A number of important drugs have been identified as substrates, inducers and/or inhibitors of CYP3A4. The ability of drugs to act as inducers, inhibitors, or substrates for CYP3A is predictive of whether concurrent administration of these compounds with a known CYP3A substrate might lead to altered drug disposition, efficacy or toxicity. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein (P-gp). To date, the identified clinically important CYP3A4 inhibitors mainly include macrolide antibiotics (e.g., clarithromycin, and erythromycin), anti-HIV agents (e.g., ritonavir and Delavirdine), antidepressants (e.g. fluoxetine and fluvoxamine), calcium channel blockers (e.g. verapamil and diltiazem), steroids and their modulators (e.g., gestodene and mifepristone), and several herbal and dietary components. Many of these drugs are also mechanism-based inhibitors of CYP3A4, which involves formation of reactive metabolites, binding to CYP3A4 and irreversible enzyme inactivation. A small number of drugs such as rifampin, phenytoin and ritonavir are identified as inducers of CYP3A4. The orphan nuclear receptor, pregnane X receptor (PXR), have been found to play a critical role in the induction of CYP3A4. The inhibition or induction of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs and the patients. The study of interactions of newly synthesized compounds with CYP3A4 has been incorporated into drug development and detection of possible CYP3A4 inhibitors and inducers during the early stages of drug development is critical in preventing potential drug-drug interactions and side effects. Clinicians are encouraged to have a sound knowledge on drugs that behave as substrates, inhibitors or inducers of CYP3A4, and take proper cautions and close monitoring for potential drug interactions when using drugs that are CYP3A4 inhibitors or inducers.
Population pharmacokinetics of Delavirdine and N-delavirdine in HIV-infected individuals
Clin Pharmacokinet 2005;44(1):99-109.PMID:15634033DOI:10.2165/00003088-200544010-00004.
Objective: Delavirdine is a non-nucleoside reverse transcriptase inhibitor used in combination regimens for the treatment of HIV-1 infection. Our objective was to characterise the population pharmacokinetics of Delavirdine in HIV-infected patients who participated in the adult AIDS Clinical Trials Group (ACTG) 260 and 261 studies. Methods: ACTG 261 was a randomised, double-blind study of Delavirdine 400mg three times daily, in various combination regimens; ACTG 260 was a concentration-targeted monotherapy study. Two hundred and thirty-four patients, and 1254 and 1251 plasma concentrations for Delavirdine and N-delavirdine, respectively, were available for population pharmacokinetic analysis. The pharmacokinetic model (and initial parameters), based on previous studies, included two compartments for Delavirdine (peripheral and central) and parallel clearance pathways (nonlinear conversion to N-delavirdine and first order clearance from the body). The model was one compartment for N-delavirdine with first order clearance. Diurnal variation of Delavirdine and N-delavirdine oral clearance was modelled as a cosine function, with amplitude variation a fitted parameter. Pharmacokinetic parameter estimates were derived from iterative two-stage analysis; observed Delavirdine and N-delavirdine concentrations fit with weighting by the inverse observation variance. Covariates were analysed by multiple general linear modelling. Results: The mean (percent coefficient of variation [%CV]) CD4 count was 315 (109) cells/mm(3), weight 76.9 (14.7) kg, age 37 (8.5) years, and 15% of the population were women. Mean (%CV) population pharmacokinetic parameter estimates for Delavirdine were: volume of distribution at steady state 67.6 (100) L, intrinsic oral clearance 19.8 (64) L/h, concentration at half the maximum velocity of metabolism (V(max)) 6.3 (69) micromol/L and first order oral clearance 0.57 (86) L/h. For N-delavirdine, the mean (%CV) apparent volume of distribution was 24.7 (75) L and apparent clearance 29.7 (42) L/h. The mean V(max) was 1376 (68) mg/day. The final model for average intrinsic clearance of Delavirdine included race, sex, weight and age as significant covariates (p < 0.05); however, these covariates do not explain a significant proportion of the overall variability in the population. Conclusions: Delavirdine disposition exhibits nonlinear pharmacokinetics and large interpatient variability, and is significantly altered by time of day (impacting potential therapeutic drug monitoring and future pharmacokinetic study designs). Although race and sex appear to influence Delavirdine pharmacokinetics, men and women and patients of different races should receive similar mg/kg dosage regimens. The presence of large interpatient variability supports the further investigation of the utility of therapeutic drug monitoring for Delavirdine, if target drug concentrations can be better defined.
Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor
Adv Exp Med Biol 1996;394:279-89.PMID:8815692DOI:10.1007/978-1-4757-9209-6_25.
In summary, DLV has been well-tolerated in > 1,000 HIV-1 infected patients. Skin rash is the most prevalent medical event associated with DLV therapy. The rash can be successfully dosed through or rechallenged in > 85% of patients. The pharmacokinetics are non-linear as DLV is metabolized primarily by cytochrome P4503A in the liver. Serum levels of DLV +/- 10 microM can easily be achieved in most HIV-1 patients, which are 100 fold above the in vitro IC90 activity. In clinical trials, DLV inhibits viral replication as demonstrated by positive surrogate marker responses (CD4 counts, P24 antigen concentration, PMBC and plasma virus titers, and plasma HIV RNA concentration). Susceptibility of HIV-1 strains to DLV decrease over time in a majority of subjects in which virus can be cultured. However, HIV strains from about 80% of subjects had a DLV IC50 < 10 microM (the trough DLV concentration in plasma) throughout the Upjohn trial. In HIV strains from about 20% of subjects, susceptibility to DLV remained unchanged in the first 8 months of DLV combination therapy, or HIV-1 was not recovered at all or most timepoints. In contrast, development of resistance to nevirapine or L-697,661 monotherapy or combination therapy with ZDV has occurred in the first eight weeks of therapy. The most common genotypic mutations seen to date are K103N and P236L. The clinical significance of the phenotypic, genotypic and surrogate marker changes associated with DLV remain to be elucidated. The surrogate marker responses in clinical trials suggest that DLV has clinical synergy with ZDV +/- ddI as evidenced by a better and more sustained surrogate marker response when a subject is sensitive to or naive to the nucleoside RTI combined with DLV. Future therapy with DLV will likely be in combination with one or more nucleoside or non-nucleoside RTIs, protease inhibitors and/or immunomodulatory agents.