The are also eliminated in faeces. Upon

Thetherapeutic concentration of OC must be attained at all sites of infection andsustain for the period of dosing interval to limit the viral load andreplication.  For this rationale, the pharmacokineticprofiles of oseltamivir and OC has been broadly studied in healthy individualsand infected patients.  Inter- andintra-subject variability across different geographic populations has also beenstudied. Absorption, distribution,metabolism and elimination Upon oral administrationof OP, oseltamivir is absorbed from the gastrointestinal tract and converted toactive metabolite OC by hepatic esterases and gives an absolute bioavailabilityof 80%. OC is noticeable within 30 min of dosing, and its concentration reachnear maximal level in 3-4 hours and exceeds the oseltamivir concentration by 20fold. The plasma concentration of OC exhibit minimal inter and intra subjectvariability  and the associated foodintake has little effect on its bioavailability.

The absorption rate of oseltamiviris impassive under altered gastric pH and that induced by cimetdine andantacids.  The amount of circulationof OC after intravenous administration in man is 23-26 L. This value iscomparable of extracellular volume of body water in humans, signifying that themetabolite may penetrate infection site at volume similar to those in plasma.

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In reality, oseltamivir and OC are relatively distributed with therapeuticconcentration reachin in lung, trachea and nasal mucosa, as well as the sinusesand middle ear. OC reached the lung and was detected in bronchoalveolar liningfluid with more or less exposure to that in plasma and a slower clearance  in rats as confirmed by Eisenberg Oral administration of theprodrug results in 75% conversion in to OC by first-pass metabolism and 5% isrecovered in urine as OP. In in-vitro, neither of the drug interacts with humancytochrome P450 mixed function oxidases or glucuronyl transferases. Theelimination of OP and OC are mainly by renal excretion but small amounts arealso eliminated in faeces.  Upon oraladministration of oseltamivir, the plasma concentration decrease rapidly (halftime of 1-3 h) , though OC concentrations remain for longer (half time of 6-10h), permitting two-dose daily. Renal clearance of both the compounds go abovethe glomerular filtration rate, signifying that renal tubular secretioncontributes to elimination; for OC, this has been shown to continue via theanionic transport process.  A high safety margin forOseltamivir have been shown in acute, subacute and chronic toxicity studies4.

 Dosing of oseltamivir till 500mg twice dailyresults in pharmacokinetics which are linear and dose proportional. Before theattainment of steady state, the accumulation of OC is noted to above 2 fold.  The pharmacokinetics of multiple dosing can beenvisage from single dosing and it provides no sign of temporal change in the characterof either oseltamivir or OC Daily dosing of OC twiceresults in a steady state plasma concentration with 2-3 days. An latest research on pharmacokinetics of highdoses of oseltamivirs was studied in healthy Thai individuals.

In adose-escalation study, 21 individuals got single doses of oseltamivir atrangeof 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 foroseltamivir and 5.

1 (4.7–5.7) h for OC.

One patient confirmed reducedconversion of oseltamivir into OC due to impaired carboxylesterase activity.  


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