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Adefovir
PMEA · 9-[2-(PHOSPHONOMETHOXY)ETHYL]ADENINE · GS-393 · gs0393 · Adefovi · ADEFOVIR · A Duff Vee · Adefovir98%
Identifikatoren & physikalische Daten
| CAS No. | 106941-25-7 |
|---|---|
| Summenformel | C8H12N5O4P |
| Durchschnittliche Molmasse | 273,19 g/mol |
| Monoisotopische Masse | 273,06269049 g/mol |
| SMILES | Nc1ncnc2c1ncn2CCOCP(=O)(O)O |
| InChIKey | SUPKOOSCJHTBAH-UHFFFAOYSA-N |
| PubChem CID | 60172 |
| ChEMBL | CHEMBL484 |
| ChEBI | CHEBI:2469 |
| EC No. | 600-789-7 |
| DTXSID | DTXSID6046214 |
Chemische & physikalische Eigenschaften
| XLogP | -2 |
|---|---|
| Polarare Oberfläche (TPSA) | 136 |
| H-Brücken-Donoren | 3 |
| H-Brücken-Akzeptoren | 8 |
| Frei drehbare Bindungen | 5 |
| Schwere Atome | 18 |
| Formalladung | 0 |
| Komplexität | 327 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| Color/Form | Off-white crystalline solid |
| Löslichkeit | MW: 501.47. Off-white crystalline powder. Solubility in water (mg/mL): 19 (pH 2.0)0.4 (pH 7.2)log Kow (octanol/aqueous phosphate buffer): 1.91 /Adefovir di(pivaloyloxymethyl) ester/0.1 M NaOH: ≥5mg/mL |
| Human Drugs | Breast FeedingLactationAntiviral AgentsReverse Transcriptase Inhibitors |
| Decomposition | When heated to decomposition it emits toxic fumes of nitrogen oxides and phosphorus oxides. |
| Schmelzpunkt | >250 °C>260°C |
| Dissociation Constants | pKa1 = 2.0pKa2 = 6.8 |
| Siedepunkt | 632.5±65.0 °C(Predicted) |
| Dichte | 1.88 |
| Lagerbedingungen | -20°C |
| pKa (Säurekonstante) | pKa1 2.0, pKa2 6.8(at 25℃) |
| Aggregatzustand | powder |
| Farbe | white to beige |
| InChI | 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) |
| InChIKey | SUPKOOSCJHTBAH-UHFFFAOYSA-N |
| SMILES | P(COCCN1C2C(N=C1)=C(N)N=CN=2)(=O)(O)O |
| CAS Datenbank | 106941-25-7(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]P264, P270, P301+P316, P321, P330, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 41 reports by companies from 2 notifications to the ECHA C&L Inventory. |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including adefovir dipivoxil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Adefovir dipivoxil/ |
| Hazard Classes and Categories | Acute Tox. 3 (97.6%) |
| Lagerbedingungen | Store in original container at 25 °C (77 °F), excursions permitted to 15-30 °C (59-86 °F). |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash. |
| Wechselwirkungen | 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 adefovirdipivoxilno 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). |
| 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. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks have been associated with gastrointestinal side effects./CASE REPORTS/ This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors./CASE REPORTS/ A 56-year-old male patient received adefovir dipivoxil (10 mg/day) for chronic hepatitis B resistant to lamivudine. On the fifth week of treatment, the platelet count dropped to 26 x 10(3) mm(-3)anti-platelet antibodies were detectable in serum. The drug was discontinued and the platelet count improved spontaneously. A re-challenge with adefovir caused a new episode of thrombocytopenia, again after a five-week treatment period. To date, thrombocytopenia has not been described after adefovir therapy for chronic hepatitis B and seems to be a rare event./CASE REPORTS/ Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphatemic osteomalacia. /Investigators/ diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. ...For more Human Toxicity Excerpts (Complete) data for Adefovir (11 total), please visit the HSDB record page. |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)adefovirDILI PositiveOralDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3-10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day./LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Long-term oral carcinogenicity studies of adefovir dipivoxil in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection. In both mouse and rat studies, adefovir dipivoxil was negative for carcinogenic findings./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When pregnant rats were administered intravenous adefovir at maternally toxic doses associated with systemic exposure 38 times that in humans, embryotoxicity and an increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia, and kinked tail) were observed. No adverse effects on development were seen with intravenous adefovir administered to pregnant rats at a systemic exposure 12 times that in humans./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Animal reproduction studies were conducted in rats and rabbits with orally administered adefovir dipivoxil and intravenously administered adefovir. In rats and rabbits, no embryotoxicity or teratogenicity was shown from oral administration of adefovir dipivoxil at maternal doses producing systemic exposures approximately 23 times (rats) and 40 times (rabbits) that achieved in humans at the therapeutic dose of 10 mg/day.For more Non-Human Toxicity Excerpts (Complete) data for Adefovir (7 total), please visit the HSDB record page. |
| Populations at Special Risk | Use with caution /in geriatric patients/ because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.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. |
| Antidote and Emergency Treatment | If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Following a 10 mg single dose of adefovir, a four-hour hemodialysis session removed approximately 35% of the adefovir dose.Removed by hemodialysiseffect of peritoneal dialysis unknown./SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B//SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B//SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/ |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | 2811 |
| Zollcode | 29339900 |
| RTECS-Nr. | SZ6563500 |
| R-Sätze (R) | 25 |
| Gefahrensymbole | T |
| Sicherheitshinweise (S) | 45 |
| Gefahrenklasse | 6.1Acute Tox. 3 Oral |
| Verpackungsgruppe | Ⅲ |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 106941-25-7(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
Adefovir has been used to study its anti-retro viral effect on porcine endogenous retrovirus (PERV) activity.