Bioavailability calculation methods

For drugs with zero oral bioavailability this method also provides a direct estimate of the pulmonary deposition efficiency of the device. For drugs with distinct oral bioavailability, this method, combined with charcoal-block, enables calculation of both pulmonary and oral availabilities [86],... 

Many studies point to the significance of conformational factors in influencing solubility, partitioning, and even bioavailability of flexible com-pounds. 0 54,55,158-160 Because the above-described log P calculation methods are based on a static view of molecular structure, they will fail to model adequately dynamic equilibrium properties such as lipophilicity and biodistribution. There are at least two distinct ways to approach the lipophilic behavior of flexible compounds ... 

A., Comparison of methods to calculate cyclosporine A bioavailability from consecutive oral and intravenous doses,/. Pharmacokinet. Biopharm. 

The TGD has noted that in practice, relevant data on kinetics and metabolism, especially after dermal and inhalation exposure, are frequently missing. As a consequence, corrections can only be made for differences in bioavailability. There are some pragmatic approaches in order to calculate a NAEL (or LAEL) by extrapolation, when specific data are not available. The methods described are for extrapolating from oral toxicity data since this is the route most often used for repeated dose toxicity studies in animals. The TGD emphasized that it should be noted that insight into the reliability of the current methodologies for route-to-route extrapolation has not been obtained yet, with a reference to the smdy performed by WUschut et al. (1998), see above. 

Blood samples were taken at 0.25, 0.5, 1.5, 2.5, 4.5, 6.5, 8.5, 10.5 and 12.5 h and the concentration of theophylline in serum was assayed by a spectrophotometric method [7]. The samples were analysed in duplicate. Bioavailability was calculated from the area under the concentration curve following the trapezoidal rule. 

There are several properties of a chemical that are related to exposure potential or overall reactivity for which structure-based predictive models are available. The relevant properties discussed here are bioaccumulation, oral, dermal, and inhalation bioavailability and reactivity. These prediction methods are based on a combination of in vitro assays and quantitative structure-activity relationships (QSARs) [3]. QSARs are simple, usually linear, mathematical models that use chemical structure descriptors to predict first-order physicochemical properties, such as water solubility. Other, similar models can then be constructed that use the first-order physicochemical properties to predict more complex properties, including those of interest here. Chemical descriptors are properties that can be calculated directly from a chemical structure graph and can include abstract quantities, such as connectivity indices, or more intuitive properties, such as dipole moment or total surface area. QSAR models are parameterized using training data from sets of chemicals for which both structure and chemical properties are known, and are validated against other (independent) sets of chemicals. 

Of the various methods that may be used to determine bioavailability for ASOs, the best refer to tissue levels as the most relevant metric for calculating an estimate of absolute bioavailability. As mentioned in Chapter 4, ASOs distribute rapidly to the tissues, with an extremely slow transfer rate back into the central circulation. In addition, the elimination of ASOs occurs predominantly by nucleases in the tissue compartment. Thus, bioavailability based on plasma concentrations does not provide an accurate estimate of absolute bioavailability for ASOs if plasma concentrations cannot be quantified at extremely low concentrations for a prolonged period of time to adequately assess systemic exposure. The direct use of tissue levels in combination with physiologic pharmacokinetic modeling, however, may allow the accurate determination of bioavailability for ASOs. 

Empirical, semiempirical, and ab initio methods have been used extensively to calculate molecular descriptors. These molecular property descriptors help capture important characteristics of compounds such as bioavailability and receptor affinity. Descriptors such as octanol-water partition coefficient (log P), HOMO/LUMO energies, hammett a, total energy, heats of formation, ionization potential, atomic charges, electron densities, dipole/quadrupole moments, volume, and polar surface area are common examples. For an excellent review of physicochemical descriptors, the reader is directed to the following reference. ... 

Norinder, U., Haeberlein, M. Calculated molecular properties and multivariate statistical analysis in absorption prediction, in Drug Bioavailability, Methods and Principles in Medicinal Chemstry, Vol. 18, Van de Waterbeemd, H., Lennemas, H., Artursson, P. (eds.), Wiley-VCH, Wein-heim, 2003, pp. 358-405. 

The relative oral bioavailabilities were calculated by measuring the pharmacological effect of the compounds. This is called the pharmacodynamic method of determining pharmacokinetic parameters. Only relative oral bioavailabilities can be determined in this manner. In order to be able to determine the absolute oral bioavailability pharmacokinetic experiments are necessary. DD9812 showed a relative oral bioavailability of 10-100 %. (-)-5-OH-DPAT possessed a low relative oral bioavailability of 1-3 %, which can be explained by the considerable inactivation via glucuronidation in the gut and the liver.161... 

Another approach to human bioavailability estimation is based on in vitro data using Caco-2 as a measure of permeability and human liver microsomes for metabolism estimates. These data are combined in a graphical method to get a rough estimate of human oral bioavailability [22]. In principle, but not yet proven, this method could also be applied by using calculated permeability and metabolic stability. 

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