Emtricitabine

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Emtricitabine Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Emtricitabine is a synthetic nucleoside inhibitor of HIV-1 reverse transcriptase. Its mechanism of action entails the phosphorylation of the oxathiolane carbinol function by cellular enzymes to form the corresponding 5′-triphosphate, which competes with the endogenous 2′-deoxycytidine 5′-triphosphate substrate. The in vitro activity of emtricitabine ranges from IC₅₀ of 0.00013 to 0.64 mM against lymphoblastoid cell lines, MAGI-CCR5 cell lines, and peripheral blood mononuclear cells. Emtricitabine is prepared in about 16 steps from L-gulose, from which the O–C–S carbon stereochemistry is derived in the formation of substituted key 4-O-Acetyl-1,3- oxathiolane intermediate. This intermediate is coupled with N-benzoyl-O-trimethylsilyl- 5-fluoro-cytosine in the presence of trimethylsilyl triflate. The resulting anomeric mixture is separated by silica chromatography and subjected to two deprotection steps. Emtricitabine resistant isolates (M184V/I) were cross-resistant to lamivudine (desfluoro version of emtricitabine) and zalcitabine but remained sensitive to abacavir, didanosine, stavudine, tenofovir, zidovudine, and non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, and nevirapine). In a 48-week clinical trial using emtricitabine with didanosine and efavirin versus stavudine, didanosine and efavirenz produced 81 versus 68% responder rate respectively. In one study, 37.5% of treatment na?¨ve patients that were not achieving successful viral levels were found to exhibit a reduced potency toward emtricitabine. This resistance was due to M184V/I mutation in the HIV reverse transcriptase gene. Recommended dosing of emtricitabine is 200 mg (capsule) once per day. It is 93% bio-available and has a plasma half-life about 10 h, with 86% renal clearance. Side effects associated with emtricitabine treatment were generally mild to moderate and included headache, diarrhea, nausea, and rash. A generally mild and asymptomatic hyperpigmentation of the palms and/or soles was also observed.

• Chemische Eigenschaften

  White to Off-White Crystalline Solid

• Originator

  Emory University (US)

• Verwenden

  anti-Alzheimer’s treatment

• Verwenden

  Labeled Emtricitabine, intended for use as an internal standard for the quantification of Emtricitabine by GC- or LC-mass spectrometry.

• Verwenden

  A reverse transcriptase inhibitor. A nucleoside analog structurally related too lamivudine.It is an effective antiviral agent against HIV, HBV, and other viruses replicating in a similar manner. A nucleoside analog structurally related to Lamivudine (L172500).

• Definition

  ChEBI: An organofluorine compound that is 5-fluorocytosine substituted at the 1 position by a 2-(hydroxymethyl)-1,3-oxathiolan-5-yl group (2R,5S configuration). It is used in combination therapy for the treatment of HIV-1 infect on.

• Trademarks

  Emtriva (Gilead Sciences) [Note—Emtricitabine has appeared in the literature with the trivial names, (-)-FTC and FTC-(-).].

• Acquired resistance

  Resistance is associated with a substitution in the HIV-1 reverse transcriptase gene at codon 184 (M184V/I). Emtricitabineresistant isolates are cross-resistant to lamivudine. HIV-1 isolates with the K65R substitution in the reverse transcriptase coding region have reduced susceptibility.

• Allgemeine Beschreibung

  Emtricitabine is an orally active NRTI whose pharmacokineticsare favorable for once-daily administration.

• Pharmazeutische Anwendungen

  A synthetic nucleoside analog of cytosine, formulated for oral use.

• Pharmakokinetik

  Oral absorption: capsules 93%
  C_max 200 mg oral once daily: 1.8 ± 0.7 mg/L
  Plasma half-life: c. 10 h
  Volume of distribution: 1.4 ± 0.3 L/kg
  Plasma protein binding: <4%
  Absorption and distribution
  It is rapidly and extensively absorbed. There is moderate CNS penetration. The estimated semen:plasma ratio is approximately 4. There are presently no data on levels in breast milk.
  Metabolism and excretion
  It does not inhibit human cytochrome P₄₅₀ enzymes. About 80% is excreted in the urine, the rest in feces. Renal clearance is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are renally excreted. Exposure is significantly increased in renal insufficiency, but dose reductions are not generally recommended. It is unlikely that a dose adjustment would be required in the presence of hepatic impairment.

• Clinical Use

  Treatment of HIV infection (in combination with other antiretroviral drugs)

• Nebenwirkungen

  At least 10% of patients suffer headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough and rhinitis. Skin hyperpigmentation is common (≥10%) in pediatric patients. Emtricitabine competes with lamivudine for the enzymes involved in intracellular phosphorylation; their co- administration is contraindicated.

• Synthese

  Emcitritabine (VII) was discovered by researchers at Emory University and licensed to Triangle Pharmaceuticals, which started the development work before being acquired by Gilead. Because emcitritabine (VII) belongs to an important structural class of nucleosides with marketed drugs, such as 3TC, several processes for the manufacture of this class of oxathiolane nucleosides have appeared in patents and scientific literature. However, only the synthesis described in the latest patent filed for the manufacture of emcitritabine (VII) and one other efficient synthesis from the Liotta group will be described . The synthesis started with diacylation with butyryl chloride (62) of the 2-butene-1,4-diol (61) in methyl t-butylether at 0??C to room temperature in the presence of triethylamine to give diacylated product 63 in 95% yield. Ozonolysis followed by reduction with thiourea provided a mixture of hemiacetal 64 mixed with acetals, dimers and trimers in 97% yield, which was used in the next step directly. The hemiacetal mixture was reacted with thioacetic acid in toluene at 85??C for 3 hr to give the crude keto oxathiolane mixture, which was purified by vacuum distillation in a 2-in Pope Scientific wiped film still to remove impurities and collect about 92% pure 66 in 54% yield. Also mentioned in the patent is the potential use of enzymatic resolution of the isomers as reported previously. This keto oxathiolane 66 was reduced at 5??C with lithium aluminum t-butoxide, which was prepared in situ via reaction of LAH and t-butanol, and the resulting lactol was trapped with acetic anhydride in the presence of DMAP in the same reaction vessel to give, after workup, 87% yield of the key intermediate acetate 67. The bis-silyl protected 5- fluorocytosine 68, prepared in situ by reacting 5- fluorocytosine (71) with HMDS, was reacted with acetate 67 in the presence of trimethylsilyliodide at 0??C to room temperature to give a 1:1 mixture of alpha and beta-anomers 69 and 70. Pure 69 could be isolated by recrystallization from toluene. Cleavage of the butyryl group with a strongly basic DOWEX SBR resin in methanol at room temperature gave emcitritabine (VII) in 81% yield. An alternate concise synthesis reported by Liotta et al is worth mentioning. This synthetic route accessed the key thioxalane acetate 76 as the TBDMS ether in four steps from allyl alcohol 72. The key step to the preparation of the final compound was the coupling of the bis-silyl 5-fluorocytosine (68) with acetate 76 with tin tetrachloride in a stereoselective manner, after cleavage of the silyl groups and recrystallization, to give pure cis isomer emcitritabine (VII) in excellent yield.

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antivirals: avoid concomitant use with lamivudine.
  Orlistat: absorption of emtricitabine possibly reduced.

• Stoffwechsel

  There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in urine (approximately 86%) and faeces (approximately 14%). 13% of the emtricitabine dose was recovered in urine as three metabolites

Emtricitabine Upstream-Materialien And Downstream Produkte

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