Mechanism of Action of Tamiflu (Oseltamivir)
Oseltamivir functions as a neuraminidase inhibitor that specifically blocks the neuraminidase enzyme present exclusively on influenza A and B viruses, preventing viral release from infected cells and halting viral spread through the respiratory tract. 1, 2, 3
Detailed Mechanism
Prodrug Activation and Target Specificity
Oseltamivir phosphate is an ethyl ester prodrug that requires conversion by hepatic esterases to its active form, oseltamivir carboxylate (Ro 64-0802). 3, 4
At least 75% of an oral dose reaches systemic circulation as the active metabolite oseltamivir carboxylate, while less than 5% circulates as the parent compound. 3
The active metabolite specifically targets the neuraminidase (NA) surface protein, which is essential for de-aggregation and release of newly synthesized viral particles from infected host cells. 1
Enzymatic Inhibition Process
Neuraminidase normally cleaves sialic acid residues on the surface of infected cells, allowing progeny virions to disperse within mucosal secretions and infect adjacent cells. 1, 5
Oseltamivir carboxylate competitively inhibits this enzymatic cleavage, trapping newly formed viral particles at the cell surface and interrupting propagation of influenza virus within the respiratory tract. 1, 5
The median IC50 values demonstrate potent activity: 2.5 nM against influenza A/H1N1, 0.96 nM against influenza A/H3N2, and 60 nM against influenza B. 3
Virus Specificity and Limitations
Oseltamivir has zero activity against other respiratory viruses including RSV, parainfluenza, adenovirus, rhinovirus, or metapneumovirus—the mechanism is entirely virus-specific to influenza A and B only. 2, 6, 7
All clinical trials and FDA approval were conducted exclusively in patients with laboratory-confirmed influenza A or B infections. 2, 6
The drug does not interfere with cytochrome P450 enzymes or glucuronosyltransferases, minimizing drug-drug interaction potential. 3, 4
Pharmacokinetic Considerations
The active metabolite reaches detectable plasma levels within 30 minutes and achieves maximal concentrations after 3-4 hours following oral administration. 4
Oseltamivir carboxylate has a half-life of 6-10 hours and is eliminated entirely (>99%) by renal excretion without further metabolism. 3, 4
Steady-state plasma concentrations are achieved within 3 days of twice-daily dosing, with trough levels remaining above the minimum inhibitory concentration for all tested influenza strains. 4
Resistance Mechanisms
Reduced susceptibility occurs through amino acid substitutions in viral neuraminidase and/or hemagglutinin proteins, with the H275Y mutation being most clinically significant. 2, 3
Resistance development during treatment is infrequent (approximately 5.5% in pediatric studies), and no human-to-human transmission of resistant viruses has been documented. 2