The are also eliminated in faeces. Upon

The
therapeutic concentration of OC must be attained at all sites of infection and
sustain for the period of dosing interval to limit the viral load and
replication.  For this rationale, the pharmacokinetic
profiles of oseltamivir and OC has been broadly studied in healthy individuals
and infected patients.  Inter- and
intra-subject variability across different geographic populations has also been
studied.

 

Absorption, distribution,
metabolism and elimination

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Upon oral administration
of OP, oseltamivir is absorbed from the gastrointestinal tract and converted to
active metabolite OC by hepatic esterases and gives an absolute bioavailability
of 80%. OC is noticeable within 30 min of dosing, and its concentration reach
near maximal level in 3-4 hours and exceeds the oseltamivir concentration by 20
fold. The plasma concentration of OC exhibit minimal inter and intra subject
variability  and the associated food
intake has little effect on its bioavailability. The absorption rate of oseltamivir
is impassive under altered gastric pH and that induced by cimetdine and
antacids.

 

The amount of circulation
of OC after intravenous administration in man is 23-26 L. This value is
comparable of extracellular volume of body water in humans, signifying that the
metabolite may penetrate infection site at volume similar to those in plasma.
In reality, oseltamivir and OC are relatively distributed with therapeutic
concentration reachin in lung, trachea and nasal mucosa, as well as the sinuses
and middle ear. OC reached the lung and was detected in bronchoalveolar lining
fluid with more or less exposure to that in plasma and a slower clearance  in rats as confirmed by Eisenberg

 

Oral administration of the
prodrug results in 75% conversion in to OC by first-pass metabolism and 5% is
recovered in urine as OP. In in-vitro, neither of the drug interacts with human
cytochrome P450 mixed function oxidases or glucuronyl transferases. The
elimination of OP and OC are mainly by renal excretion but small amounts are
also eliminated in faeces.  Upon oral
administration of oseltamivir, the plasma concentration

decrease rapidly (half
time of 1-3 h) , though OC concentrations remain for longer (half time of 6-10
h), permitting two-dose daily. Renal clearance of both the compounds go above
the glomerular filtration rate, signifying that renal tubular secretion
contributes to elimination; for OC, this has been shown to continue via the
anionic transport process.

 

A high safety margin for
Oseltamivir have been shown in acute, subacute and chronic toxicity studies4.  Dosing of oseltamivir till 500mg twice daily
results in pharmacokinetics which are linear and dose proportional. Before the
attainment of steady state, the accumulation of OC is noted to above 2 fold.  The pharmacokinetics of multiple dosing can be
envisage from single dosing and it provides no sign of temporal change in the character
of either oseltamivir or OC

 

Daily dosing of OC twice
results in a steady state plasma concentration with 2-3 days. An latest research on pharmacokinetics of high
doses of oseltamivirs was studied in healthy Thai individuals. In a
dose-escalation study, 21 individuals got single doses of oseltamivir at
rangeof four increasing dose levels, giving a total of 125 individual series.
The tolerance limit was established at 675mg. Pharmacokinetics were dose linear,
with rapid absorption and conversion (median¼93%) into OC. Median 95%
confidence interval (CI) elimination half-lives were 1.0 (0.9–1.1) h for
oseltamivir and 5.1 (4.7–5.7) h for OC. One patient confirmed reduced
conversion of oseltamivir into OC due to impaired carboxylesterase activity.