テノホビル水和物 化学特性,用途語,生産方法
外観
白色～ほとんど白色粉末～結晶
用途
DNA ポリメラーゼによる基質
取り組みを競合的に阻害し、DNA 鎖の伸長停
止作用を示します。
用途
テノホビル（Tenofovir、テノフォビルとも）は抗ウイルス薬の一つ。ジソプロキシルエステルまたはアラフェナミド（アラニンイソプロピルエステルとのアミド＋フェノールとのエステル）のフマル酸塩として販売されている。
HIV感染症やB型肝炎の治療に用いられる。
効能
抗ウイルス薬, 逆転写酵素阻害薬
説明
Tenofovir is an analog of adenosine monophosphate that has antiviral activity. It is converted by cellular enzymes to tenofovir diphosphate, an obligate chain terminator that inhibits the activity of HIV reverse transcriptase and hepatitis B virus polymerase. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α and β and mitochondrial DNA polymerase γ. For
in vivo and cell culture use, tenofovir is supplied as a water soluble prodrug in the form of tenofovir disoproxil (fumarate) , which increases the intracellular diphosphorylated compound >1,000-
fold above the level attained with unmodified tenofovir.
化学的特性
White Crystalline Solid
来歴
Tenofovir was developed in the 1980s by Professor Antonín Holý and his team at the Institute of Organic Chemistry and Biochemistry (IOCB Prague) of the Czech Academy of Sciences. Their research focused on the design and synthesis of nucleotide analogs, aiming to develop novel compounds with antiviral activity. As an acyclic nucleotide phosphate analog, tenofovir exhibited broad-spectrum antiviral potential in vitro, but its low oral bioavailability limited its initial development. To overcome this bottleneck, collaboration with Gilead Sciences was crucial, ultimately leading to the successful development of tenofovir disoproxil fumarate (TDF) through a prodrug synthesis strategy. This prodrug was first approved by the FDA in 2001 for the treatment of HIV-1 infection, marking a significant breakthrough in its clinical application. Subsequent research further solidified its position in the treatment of chronic hepatitis B and facilitated the market launch of tenofovir alafenamide (TAF), a prodrug with superior renal and bone safety characteristics.
使用
Tenofovir is a drug used for the treatment of chronic heptatitis B as well as prevention and treatment of HIV/AIDS. It is a kind of nucleotide analog, acting as the reverse-transcriptase inhibitor (NtRTI). It inhibits the activity of HIV reverse transcriptase through competing with the natural substrate deoxyadenosine 5’-triphosphate, causing the termination of DNA chain.
定義
ChEBI: A member of the class of phosphonic acids that is methylphosphonic acid in which one of the methyl hydrogens is replaced by a [(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy group. An inhibitor of HIV-1 reverse transcriptase, the bis(isopropyloxycarbonyloxy
ethyl) ester (disoproxil ester) prodrug is used as the fumaric acid salt in combination therapy for the treatment of HIV infection.
適応症
Tenofovir disoproxil fumarate (Viread) is a prodrug of
tenofovir, a phosphorylated adenosine nucleoside analogue,
and is the only available agent of its class. It is
converted by cellular enzymes to tenofovir diphosphate,
which competes with deoxyadenosine triphosphate
(dATP) for access to reverse transcriptase and
causes chain termination following its incorporation.
Tenofovir was approved as part of a combination therapy
for HIV in adults who failed treatment with other
regimens; it appears to be effective against HIV strains
that are resistant to NRTIs.
獲得抵抗性
HIV variants with the K65R mutation and the K70E mutation
in the reverse transcriptase demonstrate reduced susceptibility
to tenofovir.
応用例（製薬）
A nucleotide analog structurally similar to adefovir.
EC
50 values for HBV, assessed in the HepG2 2.2.15 cell
line, ranged from 0.14 to 1.5 μm; the cytotoxic concentration
exceeded 100 μm. A decline in HBV DNA levels below
10
5 copies/mL at 48 weeks of therapy in 100% of patients
receiving tenofovir compared with 44% on adefovir therapy
has been reported. There are also case reports of patients with
primary resistance to adefovir responding to tenofovir.
It is generally well tolerated in patients with chronic HBV;
the most common side effects include nausea and gastrointestinal
upset, headache, dizziness, fatigue and rash.
生物活性
Selectively inhibits HIV reverse transcriptase (RNA-dependent DNA polymerase). Prevents cytotoxicity in SIV-infected C-8166 cells in vitro (IC 50 = 1.5 μ M). Antiviral agent.
薬物動態学
Oral absorption: c. 25%
C
max 300 mg once daily: 0.3 mg/L
Plasma half-life: 17 h
Volume of distribution: 1.3 ± 0.6 L/kg at 3.0 mg/kg
intravenous dose
Plasma protein binding: <0.7% (in vitro)
Absorption and distribution
Oral bioavailability is poor, but is enhanced by administration as the disoproxil prodrug. It may be taken with or without food. CSF penetration is likely to be minimal due to the anionic charge of the molecule at physiological pH. It accumulates in semen at higher concentrations than in plasma. It is not known if it is distributed into breast milk.
Metabolism and excretion
Tenofovir is not metabolized and is principally eliminated by the kidneys by a combination of glomerular filtration and active tubular secretion. In patients with renal dysfunction the dose should be adjusted accordingly.
Compounds such as cidofovir, aciclovir (acyclovir), valaciclovir, ganciclovir, valganciclovir and probenecid may compete for renal excretion. Tenofovir levels are increased when prescribed with some HIV protease inhibitors. The co-administration of tenofovir with didanosine leads to didanosine accumulation which is thought to occur through inhibition of purine nucleoside phosphorylase. This has been associated with impaired immune recovery and several cases of lactic acidosis and pancreatitis. If tenofovir is combined with didanosine the dose of didanosine should be reduced to 200 mg (<60 kg) or 250 mg (≥60 kg) per day and the patient monitored for symptoms of didanosine toxicity.
臨床応用
Chronic hepatitis B infection
副作用
In clinical trials of antiretroviral treatment-naive participants,
the most commonly reported adverse events were mild to
moderate gastrointestinal upset (nausea 8%, diarrhea 11%),
headache (14%) and depression (11%). Tenofovir has the
potential to result in nephrotoxicity, particularly through proximal
tubular damage, but the risk of clinically significant renal
dysfunction appears relatively low and seems to occur mainly
in subjects with other identifiable risks for renal impairment.
Minor elevations in serum creatinine and reductions in creatinine
clearance occur, but rarely require drug discontinuation.
A few (<0.1%) cases of osteomalacia and decreased bone
density have been reported.
テノホビル水和物 上流と下流の製品情報
原材料
準備製品