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| oseltamivir acid |
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| CHEBI:73139 |
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| A cyclohexenecarboxylic acid that is cyclohex-1-ene-1-carboxylic acid which is substituted at positions 3, 4, and 5 by pentan-3-yloxy, acetamido, and amino groups, respectively (the 3R,4R,5S enantiomer). An antiviral drug, it is used as the corresponding ethyl ester prodrug, oseltamivir, to slow the spread of influenza. |
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This entity has been manually annotated by the ChEBI Team.
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| ChemicalBook:CB6501589, ZINC000003929509 |
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InChI=1S/C14H24N2O4/c1- 4-10(5-2)20-12-7-9(14(18)19)6-11(15)13(12)16-8(3)17/h7,10-13H,4-6,15H2,1-3H3,(H,16,17)(H,18,19)/t11-,12+,13+/m0/s1 |
| NENPYTRHICXVCS-YNEHKIRRSA-N |
| CCC(CC)O[C@@H]1C=C(C[C@H](N)[C@H]1NC(C)=O)C(O)=O |
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Bronsted acid
A molecular entity capable of donating a hydron to an acceptor (Bronsted base).
(via oxoacid )
Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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antiviral drug
A substance used in the prophylaxis or therapy of virus diseases.
EC 3.2.1.18 (exo-alpha-sialidase) inhibitor
An antiviral drug targeted at influenza viruses. Its mode of action consists of blocking the function of the viral neuraminidase protein (EC 3.2.1.18), thus preventing the virus from budding from the host cell.
marine xenobiotic metabolite
Any metabolite produced by metabolism of a xenobiotic compound in marine macro- and microorganisms.
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antiviral drug
A substance used in the prophylaxis or therapy of virus diseases.
EC 3.2.1.18 (exo-alpha-sialidase) inhibitor
An antiviral drug targeted at influenza viruses. Its mode of action consists of blocking the function of the viral neuraminidase protein (EC 3.2.1.18), thus preventing the virus from budding from the host cell.
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View more via ChEBI Ontology
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(3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid
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GS 4071
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ChemIDplus
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oseltamivir carboxylate
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ChemIDplus
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Ro 64-0802
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ChemIDplus
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187227-45-8
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CAS Registry Number
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ChemIDplus
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7714446
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Reaxys Registry Number
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Reaxys
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Mulla H, Peek GJ, Harvey C, Westrope C, Kidy Z, Ramaiah R (2013)
Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support.
Anaesthesia and intensive care 41, 66-73 [PubMed:23362894]
[show Abstract]
Extracorporeal membrane oxygenation (ECMO) is known to affect pharmacokinetics and hence optimum dosing. The aim of this open label, prospective study was to investigate the pharmacokinetics of oseltamivir (prodrug) and oseltamivir carboxylate (active metabolite) during ECMO. Fourteen adult patients with suspected or confirmed H1N1 influenza were enrolled in the study. Oseltamivir 75 mg was enterally administered twice daily and blood samples for pharmacokinetic assessment were taken on day 1 and 5. A multi-compartmental model to describe the pharmacokinetics of oseltamivir and oseltamivir carboxylate was developed using a non-linear mixed effects modelling approach. The median (range) clearance of oseltamivir carboxylate was 15.8 (4.8-36.6) l/hour, lower than the reported mean value of 21.5 l/hour in healthy adults. The median (range) steady state volume of distribution of oseltamivir carboxylate was 179 (61-436) litres, much greater than healthy adults but similar to previous reports in critically ill patients. Substantial 'between subject' variability in systemic exposure to oseltamivir carboxylate was revealed; median (range) area under the curve and Cmax were 4346 (644-13660) ng/hour/ml and 509 (54-1277) ng/ml, respectively. Both area under the curve and Cmax were significantly correlated with serum creatinine (r2=0.37, P=0.02 and r2=0.29, P=0.02, respectively). Systemic exposure to oseltamivir carboxylate following the administration of enteral oseltamivir 75 mg twice daily in adult ECMO patients is comparable to those in ambulatory patients and far in excess of concentrations required to maximally inhibit neuraminidase activity of the H1N1 virus. Dosage adjustment for ECMO, per se, appears not to be necessary; however, doses should be reduced in patients with renal dysfunction. | Achenbach JE, Bowen RA (2013)
Effect of oseltamivir carboxylate consumption on emergence of drug-resistant H5N2 avian influenza virus in Mallard ducks.
Antimicrobial agents and chemotherapy 57, 2171-2181 [PubMed:23459475]
[show Abstract]
Oseltamivir carboxylate (OC) has been detected in environmental waters at various levels during recent influenza seasons in humans, reflecting levels of usage and stability of this drug. In consideration of the role of waterfowl as hosts for influenza viruses that may contribute to human infections, we evaluated the effect of consumption of low doses of OC on development of oseltamivir-resistant influenza virus mutants in mallard ducks (Anas platyrhynchos) infected with two different low-pathogenic (LP) H5N2 avian influenza viruses (AIV). We detected development of virus variants carrying a known molecular marker of oseltamivir resistance (neuraminidase E119V) in 4 out of 6 mallards infected with A/Mallard/Minnesota/182742/1998 (H5N2) and exposed to 1,000 ng/liter OC. The mutation first appeared as a minor population on days 5 to 6 and was the dominant genotype on days 6 to 8. Oseltamivir-resistant mutations were not detected in virus from ducks not exposed to the drug or in ducks infected with a second strain of virus and similarly exposed to OC. Virus isolates carrying the E119V mutation displayed in vitro replication kinetics similar to those of the wild-type virus, but in vivo, the E119V virus rapidly reverted back to wild type in the absence of OC, and only the wild-type parental strain was transmitted to contact ducks. These results indicate that consumption by wild waterfowl of OC in drinking water may promote selection of the E119V resistance mutation in some strains of H5N2 AIV that could contribute to viruses infecting human populations. | Instiaty I, Lindegardh N, Jittmala P, Hanpithakpong W, Blessborn D, Pukrittayakamee S, White NJ, Tarning J (2013)
Comparison of oseltamivir and oseltamivir carboxylate concentrations in venous plasma, venous blood, and capillary blood in healthy volunteers.
Antimicrobial agents and chemotherapy 57, 2858-2862 [PubMed:23507284]
[show Abstract]
Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for oseltamivir and 0.673 (0.564 to 0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for oseltamivir and 0.685 (0.502 to 1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood. | Kromdijk W, Sikma MA, van den Broek MP, Beijnen JH, Huitema AD, de Lange DW (2013)
Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique.
Intensive care medicine 39, 977-978 [PubMed:23443310] | Chairat K, Tarning J, White NJ, Lindegardh N (2013)
Pharmacokinetic properties of anti-influenza neuraminidase inhibitors.
Journal of clinical pharmacology 53, 119-139 [PubMed:23436258]
[show Abstract]
Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(1/2) β) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(1/2) β of approximately 3.0 hours). Peramivir is slowly eliminated (t(1/2) β of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation. | Hu ZY, Laizure SC, Meibohm B, Herring VL, Parker RB (2013)
Simple and sensitive assay for quantification of oseltamivir and its active metabolite oseltamivir carboxylate in human plasma using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry: improved applicability to pharmacokinetic study.
Journal of pharmaceutical and biomedical analysis 72, 245-250 [PubMed:23000242]
[show Abstract]
Although liquid chromatography/electrospray ionization tandem mass spectrometry-based assays have been reported for the measurement of the antiviral oseltamivir (OS) in human samples, these assays either involve complicated sample pretreatment or lack sensitivity. Here we introduce a straightforward approach to improve the assay performance for OS and its metabolite oseltamivir carboxylate (OSC) in human plasma. A very low concentration of mobile phase modifier can improve the ionization efficiency of both analytes, thus enabling a high sensitivity without any matrix effect. The fast LC gradient further increases the sensitivity by narrowing the peak width (6-9s) and eluting the analytes at higher organic content. The increased ionization efficiency and minimized matrix effects enabled us to introduce a one-step protein precipitation for sample clean-up without compromising the sensitivity. The lower limit of quantification was 0.34 ng/mL for both analytes, which was at least 3 times more sensitive than published assays that involve complicated sample pretreatment. The assay involves measurement of analytes and their stable-isotope internal standards in small-volume (30-μL) plasma. Sodium fluoride was utilized to prevent the hydrolysis of OS during and after sampling. The calibration curve was linear over the range of 0.34-1000 ng/mL. Accuracy was 95-110% and the precision was 2.2-11.0%. This method was applied successfully to the human pharmacokinetic study of OS, and can estimate the relevant pharmacokinetic parameters of OS with more accuracy. The approach utilized in the optimization of assay performance can be extended to the measurement of other drugs in biomatrices. | Vishkaee TS, Mohajerani N, Nafisi S (2013)
A comparative study of the interaction of Tamiflu and Oseltamivir carboxylate with bovine serum albumin.
Journal of photochemistry and photobiology. B, Biology 119, 65-70 [PubMed:23353784]
[show Abstract]
Oseltamivir phosphate (Tamiflu) is a pro-drug that is metabolized to its active form (Oseltamivir carboxylate), after oral administration. OC inhibits influenza A and B neuraminidases in vitro and OP inhibits influenza virus infection and replication in vitro. Serum albumin is the most abundant of the proteins in the circulatory system of a wide variety of organisms and plays an important role in the transport and deposition of many drugs. The aim of this study was to examine the interaction of BSA with Tamiflu and Oseltamivir carboxylate in aqueous solution at physiological conditions, using a constant protein concentration and various drug contents. FTIR, UV-Vis spectroscopic methods were used to determine the drugs binding mode, the binding constant and the effects of drug complexation on protein secondary structure. Structural analysis showed that OP and OC bind BSA with overall binding constants of K(OP-BSA)=1.88 (±0.16)×10(4)M(-1) and K(OC-BSA)=5.7 (±0.09)×10(2)M(-1). Drug complexation alters protein conformation by major reduction of α-helix and random coil and increase of β-sheet and turn structures that indicate a partial protein destabilization. The results suggest that BSA might act as carrier proteins for OP in delivering it to target molecules. | Freichel C, Breidenbach A, Gand L, Toot J, Weiser T, Körner A, Singer T, Prinssen E, Hoffmann G (2012)
Lack of unwanted effects of oseltamivir carboxylate in juvenile rats after subcutaneous administration.
Basic & clinical pharmacology & toxicology 110, 551-553 [PubMed:22145997] | Morimoto K, Nagami T, Matsumoto N, Wada S, Kano T, Kakinuma C, Ogihara T (2012)
Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats.
The Journal of toxicological sciences 37, 1217-1223 [PubMed:23208436]
[show Abstract]
Oseltamivir, a prodrug of the neuraminidase inhibitor [3R, 4R, 5S]-4-Acetamide-5-amino-3-(1-ethylpropyl)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), is widely used for treatment of influenza infections in Japan, but may be associated with mental instability and suicidal tendencies as a rare side effect, especially in infants and young patients. We examined developmental changes in the brain distribution of oseltamivir and Ro 64-0802, and in the expression of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in rats by 8 weeks. Brain concentration and Kp(,app,brain) (brain-to-plasma concentration ratio) of oseltamivir were highest in 2-week-old rats (1.45 µg/g brain and 0.14, respectively), and were negatively correlated with both age and P-gp expression at the BBB. In contrast, brain concentration and Kp(,app,brain) of Ro 64-0802 after oral gavage of oseltamivir were lowest in 2-week-old rats (0.02 µg/g brain and 0.02), and increased with age. Mass imaging analysis revealed that both compounds were distributed homogenously in brain cross-sections, including the hippocampus. From these results, it was estimated that oseltamivir concentration throughout the brain cross-sections was 70-fold and 0.9-fold higher than that of Ro 64-0802 in 2-week-old and 8-week-old rats, respectively. Such developmental changes of prodrug/drug concentration ratio, if they also occur in humans, may provide a rational basis for the putative central nervous system (CNS) side effects in young patients. | Heinig K, Wirz T, Bucheli F, Gajate-Perez A (2011)
Determination of oseltamivir (Tamiflu®) and oseltamivir carboxylate in dried blood spots using offline or online extraction.
Bioanalysis 3, 421-437 [PubMed:21338262]
[show Abstract]
BackgroundUsing dried blood spots (DBS) for quantitation of the antiviral drug oseltamivir (Tamiflu(®)), an ester prodrug, and its active metabolite oseltamivir carboxylate could provide ethical and logistic benefits. Hence, its feasibility was investigated using a previously developed column-switching LC-MS/MS method.ResultsSensitivity, precision and accuracy in DBS were comparable to standard plasma assays. Chemically treated cards provided enhanced ex vivo stability of the ester prodrug in rodent blood. Online extraction was realized using the manual TLC-MS interface or the fully automated Sample Card and Prep system. Rat pharmacokinetic study data showed good correlation between plasma, liquid blood and DBS.ConclusionFrom a bioanalytical perspective, DBS is potentially suited for Tamiflu analysis in animals and humans. Automation of the process by online DBS extraction promises workload reduction and throughput increase. | Gonçalves C, Pérez S, Osorio V, Petrovic M, Alpendurada MF, Barceló D (2011)
Photofate of oseltamivir (Tamiflu) and oseltamivir carboxylate under natural and simulated solar irradiation: kinetics, identification of the transformation products, and environmental occurrence.
Environmental science & technology 45, 4307-4314 [PubMed:21495632]
[show Abstract]
In this work the photodegradation pathways and rates of oseltamivir ester (OE) and oseltamivir carboxylate (OC) were studied under artificial and natural solar irradiation with the goal of assessing the potential of photolysis as a removal mechanism in aquatic environments. The structures of the photoproducts of OE, elucidated by ultra performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-QToF-MS), were proposed to originate from hydration of the cyclohexene ring (TP330), ester hydrolysis (TP284), a combination thereof (TP302), intramolecular cyclization involving the ester (TP312), and cleavage of the ethylpropoxy side chain (TP226). The only photoproduct detected in case of OC was postulated to correspond to the hydration of the α,β-unsaturated acid (TP302). Under simulated solar irradiation the degradation rate of OC was approximately 10 times slower than that of OE, with half-lives ranging from 48 h in ultrapure water to 12 h in surface water from Sant Joan Despi, Llobregat river. The photodegradation under natural solar irradiation during the season of pandemic Influenza peak incidence was about 150 days for OC and 15 days for OE. In general, the photoproducts proved to be more resistant toward further photodegradation than the parent antivirals. In a monitoring survey of surface waters from the Ebro river (NE Spain), OC and OE were detected along with the photoproducts TP330 and 312. | Nafisi S, Vishkaee TS (2011)
Study on the interaction of tamiflu and oseltamivir carboxylate with human serum albumin.
Journal of photochemistry and photobiology. B, Biology 105, 34-39 [PubMed:21803598]
[show Abstract]
Oseltamivir phosphate (OP; tamiflu) is an antiviral pro-drug, which is hydrolyzed hepatically to the active metabolite oseltamivir carboxylate (OC). It is the first orally neuraminidase inhibitor that was used in the treatment and prophylaxis of influenza virus A and B infection. Human serum albumin (HSA) is the most abundant of the proteins in the blood plasma and is major transporter for delivering several drugs in vivo. This study was designed to examine the interaction of HSA with oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) in aqueous solution at physiological conditions, using a constant protein concentration and various drug contents. FTIR, UV-Vis spectroscopic methods were used to determine the drugs binding mode, the binding constant and the effects of drug complexation on protein secondary structure. Structural analysis showed that OP and OC bind HSA via polypeptide polar groups with overall binding constants of K(OP-HSA)=3.86(± 1.05)× 10(3)M(-1) and K(OC-HSA)=1.5(±0.45) × 10(2)M(-1). The alterations of protein secondary structure are attributed to a partial destabilization of HSA on drug complexation. The protein secondary structure showed no major alterations at low drugs concentrations (50 μM), whereas at higher content (1mM), decrease of α-helix from 58% (free HSA) to 38% (OP-HSA)-48% (OC-HSA), decrease of random coil from 15% (free HSA) to 2% (OP-HSA)-3% (OC-HSA), increase of β-sheet from 6% (free HSA) to 20% (OC-HSA)-29% (OP-HSA) and turn from 8% (free HSA) to 17% (OC-HSA)-19% (OP-HSA) occurred in the drug-HSA complexes. These observations indicated that low drug content induced protein stabilization, whereas at high drug concentration, a partial protein destabilization occurred in these drug-HSA complexes. | He G, Massarella J, Ward P (1999)
Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.
Clinical pharmacokinetics 37, 471-484 [PubMed:10628898]
[show Abstract]
Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza. |
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