How Tamiflu (Oseltamivir) Works
Mechanism of Action
Oseltamivir works by blocking the influenza virus neuraminidase enzyme, which is essential for releasing newly formed viral particles from infected cells, thereby interrupting the spread of infection within the respiratory tract. 1, 2
Oseltamivir is administered as an inactive prodrug (oseltamivir phosphate) that requires conversion to its active form:
Prodrug activation: After oral ingestion, oseltamivir phosphate is rapidly converted by esterases (primarily in the liver) into the active metabolite oseltamivir carboxylate (Ro 64-0802). 2, 3
Target enzyme inhibition: The active metabolite selectively inhibits the neuraminidase (NA) surface protein present on both influenza A and B viruses. 1, 2
Viral replication blockade: Neuraminidase is essential for cleaving sialic acid residues, which allows newly synthesized viral particles to detach from infected host cells and spread to adjacent cells. By inhibiting this enzyme, oseltamivir prevents viral de-aggregation and release, effectively trapping new virions at the cell surface and halting propagation through the respiratory tract. 1, 2
Pharmacokinetic Profile
The active metabolite reaches therapeutic concentrations rapidly and maintains antiviral activity throughout the dosing interval:
Absorption and bioavailability: Oseltamivir is readily absorbed from the gastrointestinal tract with 80% absolute bioavailability of the active metabolite. The active form is detectable in plasma within 30 minutes and reaches peak concentrations after 3–4 hours. 3, 4
Distribution: The active metabolite penetrates all sites of influenza infection, including lung tissue, nasal mucosa, and middle ear, at concentrations sufficient to inhibit viral replication. 3, 4
Elimination: The active metabolite has a half-life of 6–10 hours and is eliminated primarily through renal excretion via both glomerular filtration and active tubular secretion. 3, 4
Steady-state concentrations: With twice-daily dosing of 75 mg, steady-state plasma trough concentrations remain above the minimum inhibitory concentration for all tested influenza strains, achieved within 3 days of treatment. 3
Spectrum of Antiviral Activity
Oseltamivir is active against both influenza A and B viruses, unlike older M2 inhibitors (amantadine, rimantadine) which only target influenza A. 1
The median IC₅₀ values demonstrate potent activity: 2.5 nM for influenza A/H1N1, 0.96 nM for influenza A/H3N2, and 60 nM for influenza B. 2
In cell culture, the effective concentrations (EC₅₀ and EC₉₀) range from 0.0008 to >35 micromolar, though these values vary depending on assay methodology and viral strain tested. 2
Clinical Implications of the Mechanism
Because oseltamivir blocks viral release rather than initial infection, it is only effective during active viral replication:
Treatment must be initiated within 48 hours of symptom onset for maximum benefit, as this corresponds to the peak viral replication phase. 1, 5
Earlier treatment provides greater benefit: initiation within 12 hours reduces illness duration by an additional 74.6 hours compared to treatment started at 48 hours. 5
The drug reduces both the quantity and duration of viral shedding compared to placebo, though the clinical significance of this reduction remains incompletely defined. 1, 6
Important Mechanistic Limitations
Oseltamivir does not prevent initial viral entry into cells or eliminate established infection—it only prevents spread to new cells:
The drug has no activity against influenza viruses that have already completed replication cycles before treatment initiation. 1, 2
Resistance can develop through amino acid substitutions in the neuraminidase enzyme (most notably H275Y in N1 strains) or hemagglutinin protein, which reduce drug binding affinity. 2
The relationship between in vitro neuraminidase inhibition and clinical efficacy in humans has not been fully established, though clinical trial data consistently demonstrate benefit. 2