General
Preferred name
TENOFOVIR DISOPROXIL
Synonyms
TENOFOVIR DISOPROXIL FUMARATE ()
Tenofovir DF ()
GS-1278 Disoproxil Fumarate ()
Viread ()
Truvada-tenofovir disoproxil fumarate ()
Tenofovir Disoproxil (fumarate) ()
TENOFOVIR DISOPROXIL ASPARTATE ()
Bis(POC)-PMPA (fumarate) ()
GS 4331 (fumarate) ()
Bis(POC)-PMPA ()
GS 4331 ()
Tenofovir (GS 1278) Disoproxil Fumarate ()
Tenofovir DF,GS-1278 Disoproxil Fumarate ()
Bis(POC)-PMPA, GS 4331 ()
Virea ()
PMPA ()
Tenofoviri disoproxili fumaras ()
GS-1278 ()
GS-4331-05 ()
GSK548470 ()
PMPA Prodrug ()
PMPA-PRODRUG ()
Tenofovir ()
GSK-548470 ()
GS-4331-05- ()
(r)-bis(poc)pmpa ()
Tenofovir bis(isopropyloxycarbonyloxymethyl) ester ()
Bis-poc-pmpa ()
GS-4331 ()
Ckd-390 ()
Bis-poc-pmpa aspartate ()
Gs 4331 aspartate ()
P&D ID
PD014778
CAS
202138-50-9
201341-05-1
Tags
prodrug
drug candidate
natural product
drug
available
Approved by
EMA
FDA
First approval
2001
Drug Status
investigational
approved
Drug indication
Discovery agent
Chronic hepatitis B infection
Max Phase
Phase 4
Phase 3
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
ROE
Following IV administration of tenofovir, approximately 70â80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion [FDA label]. There may be competition for elimination with other compounds that are also eliminated by the kidneys.
PHARMACODYNAMICS
This drug prevents viral DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections [A174637], [A174640]. **In vitro effects** The antiviral activity of tenofovir against in laboratory and clinical isolates of HIV-1 was studied in lymphoblastoid cell lines, primary monocyte/macrophage cells, in addition to peripheral blood lymphocytes. The EC50 (50% effective concentration) values of tenofovir against HIV-1 virus ranged between 0.04 μM to 8.5 μM. **Combination of tenofovir disoproxil with other drugs** In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive and synergistic effects were seen. Tenofovir demonstrated antiviral activities in cell cultures against HIV-1 [FDA label].
MOA
Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication [FDA label]. Tenofovir disoproxil fumarate is the fumarate salt of the prodrug _tenofovir disoproxil_. Tenofovir disoproxil is absorbed and converted to its active form, _tenofovir_, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, _tenofovir diphosphate_, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5â-triphosphate) and, after integration into DNA, causes viral DNA chain termination [F3442], [FDA label]. **A note on resistance** HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a _K65R_ substitution in reverse transcriptase and showed a 2â 4 fold decrease in susceptibility to treatment with tenofovir [FDA label].
INDICATION
Tenofovir is indicated in combination with other antiretroviral agents for the management of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older [FDA label]. This drug is also a component of multiple products used for the management of HIV-1 infection [F3418], [F3421]. Safety and effectiveness of tenofovir disoproxil in pediatric patients younger than 2 years of age has not been established to this date [FDA label].
METABOLISM
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug _tenofovir disoproxil_. Tenofovir disoproxil is absorbed and converted to its active form, _tenofovir_, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, _tenofovir diphosphate_, a chain terminator, by constitutively expressed enzymes in the cell [FDA label]. Two phosphorylation steps are required to convert tenofovir disoproxil to the active drug form [A174625]. The cytochrome P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir [FDA label].
ABSORPTION
After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir [F3442]. Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-â of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μgâ¢hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled [FDA label].
HALF-LIFE
When a single oral dose is given, the terminal elimination half-life is approximately 17 hours [FDA label].
ABSORPTION
After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir [F3442].; ; Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-â of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μgâ¢hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled [FDA label].
PHARMACODYNAMICS
This drug prevents viral DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections [A174637], [A174640].; ; **In vitro effects**; ; The antiviral activity of tenofovir against in laboratory and clinical isolates of HIV-1 was studied in lymphoblastoid cell lines, primary monocyte/macrophage cells, in addition to peripheral blood lymphocytes. The EC50 (50% effective concentration) values of tenofovir against HIV-1 virus ranged between 0.04 μM to 8.5 μM. ; ; **Combination of tenofovir disoproxil with other drugs**; ; In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive and synergistic effects were seen. Tenofovir demonstrated antiviral activities in cell cultures against HIV-1 [FDA label].
INDICATION
Tenofovir is indicated in combination with other antiretroviral agents for the management of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older [FDA label]. This drug is also a component of multiple products used for the management of HIV-1 infection [F3418], [F3421]. ; ; Safety and effectiveness of tenofovir disoproxil in pediatric patients younger than 2 years of age has not been established to this date [FDA label].
METABOLISM
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug _tenofovir disoproxil_. Tenofovir disoproxil is absorbed and converted to its active form, _tenofovir_, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, _tenofovir diphosphate_, a chain terminator, by constitutively expressed enzymes in the cell [FDA label]. Two phosphorylation steps are required to convert tenofovir disoproxil to the active drug form [A174625]. ; ; The cytochrome P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir [FDA label].
TOXICITY
**A note on breastfeeding** The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil [FDA label]. **Carcinogenesis** Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose [FDA label]. **Pregnancy** This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil [FDA label]. **Mutagenesis** Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice. **Impairment of Fertility** There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats [FDA label].
MOA
Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication [FDA label].; ; Tenofovir disoproxil fumarate is the fumarate salt of the prodrug _tenofovir disoproxil_. Tenofovir disoproxil is absorbed and converted to its active form, _tenofovir_, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, _tenofovir diphosphate_, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5â-triphosphate) and, after integration into DNA, causes viral DNA chain termination [F3442], [FDA label]. ; ; **A note on resistance**; ; HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a _K65R_ substitution in reverse transcriptase and showed a 2â 4 fold decrease in susceptibility to treatment with tenofovir [FDA label].
TOXICITY
**A note on breastfeeding**; ; The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil [FDA label].; ; ; **Carcinogenesis**; ; Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose [FDA label]. ; ; **Pregnancy**; ; This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. ; ; Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil [FDA label].; ; **Mutagenesis**; ; Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.; ; **Impairment of Fertility**; ; There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats [FDA label].;
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
1
Organisms
5
Compound Sets
17
AdooQ Bioactive Compound Library
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[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
61
Molecular Weight
519.17
Hydrogen Bond Acceptors
15
Hydrogen Bond Donors
1
Rotatable Bonds
13
Ring Count
2
Aromatic Ring Count
2
cLogP
3.04
TPSA
185.44
Fraction CSP3
0.63
Chiral centers
1.0
Largest ring
6.0
QED
0.23
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Microbiology&virology
Proteases/Proteasome
Anti-infection
Target
HIV reverse transcriptase
CYP1A2
HBV
HIV
Reverse Transcriptase
HIV,Reverse Transcriptase
Indication
human immunodeficiency virus (HIV-1), hepatitis B
MOA
nucleoside reverse transcriptase inhibitor
Biosynthetic Origin
Nucleoside
Therapeutic Indication
Antiviral
Therapeutic Class
Antiinfective Agents
Source data
