阿德福韦二磷酸盐除了靶向病毒 DNA 聚合酶外，还充当 DNA 终止子。首次磷酸化被发现是由腺苷酸氧化引起的，随后肌酸和ADP氧化产生阿德福韦二磷酸[1]。

阿德福韦隔膜的生物利用度为 60%，且不受食物影响。它的半衰期为 12 至 30 小时。阿德福韦没有明显的代谢产物，通过肾脏消除。一般来说，阿德福韦对细胞色素P450没有影响[3]。

Absorption, Distribution and Excretion
Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%. A single 10-mg oral dose of adefovir dipivoxil in adults results in peak adefovir plasma concentration within 0.58-4 hours.
4% or less of adefovir is bound to plasma or serum proteins.
In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 ug/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 +/- 75 and 352 +/- 9 mL/kg, respectively.
Food does not affect the area under the concentration-time curve (AUC) of adefovir.
For more Absorption, Distribution and Excretion (Complete) data for Adefovir (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) was the only metabolite formed after oral administration of bis-POM PMEA. Three metabolites were detected after oral administration of either bis-(phenyl) PMEA or bis-(o-ethoxyphenyl) PMEA to rats: PMEA, the corresponding monoester, and 2-adenylacetic acid. The major metabolite of bis-(phenyl) PMEA was 2-adenylacetic acid following oral administration. 2-Adenylacetic acid appears to have been formed from the intact prodrugs by a P450 mediated oxidation of the ethyl side chain.
Following oral administration, adefovir dipivoxil is converted to the active adefovir.
PMEA is a known human metabolite of pradefovir.

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Biological Half-Life
Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 +/- 1.65 hours.
... Diphosphorylated ... PMEA has a relatively long intracellular half-life (16-18 hr) ...

Hepatotoxicity
Serum aminotransferase elevations are common during or after therapy of hepatitis B, but appear to be due to exacerbations of the underlying HBV infection rather than hepatotoxicity. Sudden withdrawal of adefovir therapy can lead to an acute flare of hepatitis as viral levels suddenly rise. These withdrawal flares are usually transient and self-limited, but in rare instances are symptomatic and severe and can lead to death or need for liver transplantation. Instances of moderate serum aminotransferase elevations early during treatment have been described in clinical trials, but these elevations are usually transient and asymptomatic and are found in up to 25% of persons who start nucleoside analogue therapy of hepatitis B. Finally, development of antiviral resistance can be followed by a flare of the underlying hepatitis B as HBV DNA levels rise. Antiviral resistance to adefovir is rare during the first 1 to 2 years of therapy, but increasing rates are found with long-term therapy.
Adefovir has not been associated with cases of lactic acidosis with hepatic steatosis and liver failure. Tenofovir, a nucleotide analogue similar to adefovir, has been associated with isolated cases of lactic acidosis, but only in combination with other antiretroviral agents that are more closely linked to this syndrome. Because adefovir is considered contraindicated in HIV infection (it has weak anti-HIV activity), it is not used in combination with typical antiretroviral drugs. There have been no convincing cases of lactic acidosis or of clinically apparent liver injury with symptoms or jaundice due to adefovir.
Likehood score: E (unlikely cause of clinically apparent, idiosyncratic liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Adefovir has not been studied in nursing mothers being treated for hepatitis B infection. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
No differences exist in infection rates between breastfed and formula-fed infants born to hepatitis B-infected women, as long as the infant receives hepatitis B immune globulin and hepatitis B vaccine at birth. Mothers with hepatitis B are encouraged to breastfeed their infants after their infants receive these preventative measures.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
Potential increased risk of nephrotoxicity in patients receiving other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, tacrolimus, vancomycin, certain nonsteroidal anti-inflammatory agents [NSAIAs]); monitor closely.
Pharmacokinetic interaction (33% increase in peak plasma concentration and 23% increase in AUC of adefovirdipivoxil; no effect on pharmacokinetics of ibuprofen). Clinical importance unknown. May occur because of increased oral bioavailability of adefovir.
Tenofovir disoproxil fumarate and adefovir dipivoxil should not be used concomitantly for treatment of chronic HBV infection.
... Study GS-02-531 was an open-label, multicentre drug interaction trial to examine potential drug interactions between adefovir and tacrolimus in stable post-transplant recipients. Sixteen non-HBV-infected post-transplant recipients with median age 45.5 years (69% male, 44% Caucasian, 50% Hispanic and 6% Black) and stable hepatic and renal function on a stable daily dose of tacrolimus (2-10 mg total daily dose) were studied before (tacrolimus alone) and after co-administration of adefovir 10 mg daily for 14 days (Days 1-14). Pharmacokinetic (PK) analyses utilized non-compartmental methods. The median elimination half-life of tacrolimus was 14.47 and 12.59 h for Day 0 and Day 14 respectively. The geometric mean ratios for tacrolimus on Day 14 vs Day 0 were 105.2% [90% confidence interval (90% CI): 89.8-123%] for C(max) and 106.4% (90% CI: 92.9-122%) for AUC(tau). Both 90% CIs for the ratios were contained within the predefined lack of interaction bounds of 80 and 125% (i.e. within the bounds for the equivalence assessment), indicating that these PK parameters of tacrolimus are not significantly altered by co-administration of adefovir. Similarly, the observed adefovir PK parameters after 14 days of co-administration with tacrolimus were comparable to historical data in non-transplant patients receiving adefovir alone. Serum creatinine values were stable during the study period. There is no significant PK interaction between tacrolimus and adefovir co-administered to liver transplant recipients for 14 days.
Adefovir should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including TRUVADA (emtricitabine/tenofovir disoproxil fumarate combination tablet), ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet) and COMPLERA (emtricitabine/rilpivirine/tenofovir disoproxil fumarate).

[1]. 7.11 - Deoxyribonucleic Acid Viruses: Antivirals for Herpesviruses and Hepatitis B Virus. Comprehensive Medicinal Chemistry II. Volume 7, 2007, Pages 295-327.

[2]. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003 Feb 27;348(9):808-16.

[3]. 155 - Drugs to Treat Viral Hepatitis. Infectious Diseases. Volume 2, 2017, Pages 1327-1332.

Therapeutic Uses
Phosphonic Acids; Adenine/analogs & derivatives; Antiviral Agents; Reverse Transcriptase Inhibitors
Adefovir is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. /Included in US product label/
For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function. /Included in US product label/
This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. CONCLUSION: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years.

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Drug Warnings
/BOXED WARNING/ Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-Hepatitis B therapy including adefovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-Hepatitis B therapy. If appropriate, resumption of anti-Hepatitis B therapy may be warranted.
/BOXED WARNING/ In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment.
/BOXED WARNING/ HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated Human Immunodeficiency Virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with adefovir, that may have activity against HIV.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
For more Drug Warnings (Complete) data for Adefovir (20 total), please visit the HSDB record page.

C8H12N5O4P

273.18

273.062

106941-25-7

Adefovir-d4;1190021-70-5

60172

White to off-white solid powder

1.9±0.1 g/cm3

632.5±65.0 °C at 760 mmHg

>260°C

336.3±34.3 °C

0.0±2.0 mmHg at 25°C

1.769

-2.06

146.19

3

8

5

18

327

0

SUPKOOSCJHTBAH-UHFFFAOYSA-N

InChI=1S/C8H12N5O4P/c9-7-6-8(11-3-10-7)13(4-12-6)1-2-17-5-18(14,15)16/h3-4H,1-2,5H2,(H2,9,10,11)(H2,14,15,16)

((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid

GS-0393 GS-393 GS0393 GS393 GS 0393 GS 393 PMEA

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)

0.1 M NaOH : ~10 mg/mL (~36.60 mM)
H2O : ~1 mg/mL (~3.66 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。