Effect of CMF1 on the pharmacokinetics of OA and OC in rats was evaluated by comparing the pharmacokinetics profiles of OA and OC among Group 1 to Group 3 that have received various types of treatment with OA.
In comparing Groups 2 or 3 (two different doses of the CMF1 in combination with OA) with Group 1 (OA alone) (Table 3), the mean plasma concentrations of OA and OC were lower in Groups 2 and 3 than that in Group 1.
Further mechanistic studies revealed that CMF1 exhibited dose-dependent inhibition on the metabolism of OA at both 37[degrees]C and room temperature (Figure 1), with a greater % inhibition that occurred at 37[degrees]C.
These adverse events are mild and unlikely to be related to the study WM and/or WM + CMF1 treatment.
As shown in Table 3 and Figure 3, coadministration of WM + CMF1 generally lowered the mean [C.sub.max] of OA and OC in plasma, while only slightly reduction in AU[C.sub.0-12 h] was observed.
Effect of Coadministration of CMF1 with OA on the Antivirus Effect of Tamiflu
The antiviral activities of Group 1 treated with OA alone were found to be significantly enhanced when OA was used in combination with CMF1 at the dose of 1.95mg/kg (Group 2) (P = 0.006) or 3.90 mg (Group 3) (P = 0.008).
By comparing the data of Group 1A, no significant difference in the inhibitory effect was observed between WM and WM + CMF1 treatments.
In order to mimic the clinical practice of both OA and CMF1, their human equivalent doses (OA at 30 mg/kg, CMF1 at 1.95 and 3.90 g/kg), dosing frequency (5-day dosing regimen), and dosing methods (oral) have been adopted for the current rat study.
Our animal pharmacokinetic study indicated that CMF1 can significantly decrease OC concentration and urinary excretion, possibly resulting from a decrease of absorption or inhibition of presystemic metabolism of OA.
In rat studies, by comparson with those from OA alone, the [C.sub.max], urinary recovery and AUC of OC, and the OC/OA AUC ratio in OA + CMF1 groups were significantly decreased (26%-27%) in a dose-dependent manner.
To compare the antivirus effects of OA alone or in combination with CMF1 present in rat plasma by plaque reduction assay, plasma sample was required to be ultracentrifuged followed by dilution with maintenance medium in 1: 500 to avoid cytotoxicity to MDCK cells by removing the protein or the other matrix from plasma.