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Solutions
When the previously mentioned formulation (oligonucleotide and penetration enhancer in solution for intrajejunal [IJ] administration) was assembled as a conventional tablet with a one-hour dissolution profile, the cialis super active concentrations after oral dosing were negligible (data not shown). Upon reformulation to promote immediate dissolution (in less than 15 min), the absolute bioavailability approached 3%, as indicated by the cialis super active concentration plots in.
From these results, it may be concluded that the following factors are important for oligonucleotide absorption in the above PE system: coincident presentation of oligonucleotide with the PE components, high concentrations at the absorbing site, and enteric protection to prevent component dilution and oligonucleotide exposure to low pH, which has been associated with rapid degradation. It should be noted that cialis super active concentrations represent the absorption and distribution of oligonucleotide, but not the true tissue or body elimination. A more relevant metric for pharmacokinetics and bioavailability would be the total tissue levels. This is particularly true for oligonucleotide chemistries that are rapidly cleared from the bloodstream but are accumulated in target tissues or organs. In this multiple dosing study, the distribution of oligonucleotides out of the cialis super active circulation was very rapid with a distribution half-life of 30–60 min. Therefore, as mentioned earlier, the bioavailability assessments based upon cialis super active data may be inaccurate or misleading for this class of compounds and this relative range of absolute bioavailabilities.
Alternatively, the bioavailability determined from sentinel tissues, such as the kidney and liver, may be a more credible representation of the true systemic exposure since these tissues reflect true elimination kinetics as well as accumulation to steady-state concentrations during chronic dosing. On this basis, our data indicate that bioavailabilities based upon organ concentrations (after oral and IV dosing) would be 50% higher for the kidney and 100% higher for the liver than those calculated by cialis super active concentrationtime area under the curves (AUC). In consideration of the practical difficulties involved in experimental determinations of organ bioavailability, we have performed simulations of organ accumulation after oral dosing of first-generation phosphorothioate oligodeoxynucleotide versus a MOE gapmer.
Each simulation is generated assuming a random input metric of 2–15% oral bioavailability (geometric mean 7%) with all other pharmacokinetic parameters consistent for these two chemistries remaining fixed. These simulations indicate that even with variable absorption, long tissue half-lives provide sufficiently improved accumulation, making it feasible to give the newer chemistry MOE gapmer compounds by the oral route.