Oseltamivir carboxylate

Fig. 6 Superimposition of inhibitors and key active site residues from crystal structures of oseltamivir carboxylate 18 brown carbons, PDB - 2qwk) and Neu5Ac2en 4 (green carbons, PDB - IfSb) in complex with influenza A virus siaMdase. Note the alternative conformations of the...

Fig. 7 The influenza virus A sialidase active site showing the five potential inhibitor binding subsites (with S5 containing the hydrophobic pocket formed by reorientation of the Glu276 side-chain), with oseltamivir carboxylate 18 placed in the active site...

Fig. 9 Diagrammatic representation of influenza A virus active site indicating the amino acid residues that have shown mutation under drug pressure. Oseltamivir carboxylate 18 is shown in the active site...

Oseltamivir carboxylate 18 is used in sialidase inhibition assays Numbering used is that of A/N2 Abed et al. (2008)... 

Wang MZ, Tai CY, Mendel DB (2002) Mechanism by which mutations at His274 alter sensitivity of influenza a vims N1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob... 

Two classes of inhibitors for influenza virus are currently available (Hayden 2006). The M2 proton channel inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors oseltamivir carboxylate and zanamivir. Chapter 5 provides more details about the class of NA inhibitors. 

Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. 

Bartels P, von Tumpling W (2008) The environmental fate of the antiviral drug oseltamivir carboxylate in different waters. Sci Total Environ 405 215-225... 

Pharmacology Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. 

Drug resistance - In clinical studies of naturally acquired infection with influenza virus, 1.3% of posttreatment isolates in adults and adolescents, and 8.6% in children from 1 to 12 years of age showed emergence of influenza variants with decreased neuraminidase susceptibility to oseltamivir carboxylate. 

The mean Cmax oseltamivir and oseltamivir carboxylate were 65.2 ng/mL... 

Coadministration with food has no significant effect on the peak plasma concentration and the area under the plasma concentration time curve of oseltamivir carboxylate. 

Distribution - The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions. /Wefabo//sm- Oseltamivir is extensively converted to oseltamivir carboxylate by... 

Excretion - Absorbed oseltamivir is primarily (more than 90%) eliminated by conversion to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration. Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects. Oseltamivir carboxylate is eliminated entirely (more than 99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h) indicating that tubular secretion occurs, in addition to glomerular filtration. Less than 20% of an oral dose is eliminated in feces. 

Lactation It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human breast milk. Therefore, use oseltamivir only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant. 

Probenecid Coadministration of probenecid results in an approximate 2-fold increase in exposure to oseltamivir carboxylate because of a decrease in active anionic tubular secretion in the kidney. 

Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been isolated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase however, the clinical relevance of this resistance mechanism is unknown. 

Orally administered oseltamivir phosphate is rapidly absorbed and converted by hepatic esterases to oseltamivir carboxylate. Approximately 80% of an oral dose reaches the systemic circulation as oseltamivir carboxylate, with peak plasma concentrations achieved within 2.5 to 5 hours. The plasma elimination half-life of oseltamivir carboxylate is 7 to 9 hours. Elimination of the parent drug and its active metabolite occurs primarily by active tubular secretion and glomerular filtration. 

Ghosh, G.C., Nakada, N., Yamashita, N. and Tanaka, H. (2010) Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. Environ. Health Perspect., 118 (1), 103-107. 

FIGURE 17.12 Interaction of oseltamivir carboxylate (20) with the influenza virus sialidase active site. 

FIGURE 17.16 Comparison of group 1 and group 2 sialidase active sites, (a) Oseltamivir carboxylate binds into the open catalytic site of group 1 sialidase Nl. (b) Binding between oseltamivir carboxylate and group 2 sialidase N9 with the closed 150-loop. 

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