Class II compound

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

Famphur is considered a Class II toxic compound to the Japanese quail (Cotumix japonica) according to the classification of Hill and Camardese (1986). Class II compounds (very toxic) kill 50% of the test organisms on diets containing 40 to 200 mg chemical/kg ration for 5 days followed by a 3-day observation. By comparison, the 50% kill in other classes (in mg/kg diet) is <40 in Class I (highly toxic), >200 to 1000 in Class III (moderately toxic), >1000 to <5000 in Class IV (slightly toxic), and >5000 in Class V (practically nontoxic) (Hill and Camardese 1986). Smith (1987) rates famphur as a Class I toxic compound, as judged by results of dietary tests with mallards. 

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

To summarize, there are several rationales to justify the approach for permeation and dissolution testing. Nevertheless, it has to be pointed out that for the rather uncomplicated BCS class I and some BCS class II compounds, where it can be anticipated that increased luminal concentrations will lead to increased transepithelial fluxes, no significant additional information should be expected to the conventional dissolution testing. However, for difficult compounds, mainly belonging to BCS classes III and IV, important information about the drug in the dosage form can be obtained. 

Solvents restricted under the Montreal Protocol are categorized as Class 1 or Class II compounds, many of which are listed in table 7.3. Class I componnds have already undergone a major phase-ont, whereas Class II componnds will be completely phased out of use by 2030. 

Intermediate between these two extremes are minerals classified as Class II compounds in which the two sites are similar but distinguishable that is, both are octahedral sites, but with slightly different metal-oxygen distances, ligand orientation or bond-type. Examples include the amphibole Ml, M2 and M3 sites (figs 4.14 and 5.18), the mica trans-Ml and c -M2 sites (fig. 5.21) and babingtonite (Bums and Dyar, 1991). Such materials still exhibit properties of cations with discrete valences, but they have low energy IVCT bands and may be semiconductors. 

An important qualitative description of the spectral behavior of class II compounds was presented by Robin and Day. This simple model has found apphcabihty to the discussion of the spectra of numerous mixed valence compounds in which some delocalization occurs. In this model, it is assumed that the ground-state wave function contains the function, a, which describes mixing of the wave function for site A with the wave function of site B. 

With very few exceptions, dissolution of the drug substance in the GI tract milieu is a prerequisite for drug absorption following oral administration. For Class II compounds, the rate-limiting factor in their intestinal absorption is dissolution /solubility [23-25]. Hence, in-depth understanding of this process is essential in the oral delivery of low-solubility compounds. Factors governing the dissolution process can be directly identified from the following equation, based on the Nernst-Brunner and Levich modifications of the Noyes-Whitney model [26-28] ... 

For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by definition, BCS Class II compounds with weak acidic properties)... 

Apparently, it is possible to modify the biorelevant media and also the involved hydrodynamics, flow rate so as to achieve IVIVC in this particular situation. However, more studies with different BCS class II compounds are needed. 

This suggests that DCS Class I compounds are those with high solubility and high permeability based on kinetic solubility and PAMPA or Caco-2 analyses. Class II compounds are those associated with high permeability and by medium or low solubility while Class III compounds are associated with high solubility and medium or low permeability. Class IV materials have both low solubility and low permeability (Figure 4). 

A comparison of the DCS value estimated using in silica, HTS and rat in situ perfusion estimated for a given subset of clinical candidates is given in Table 1 based on internal historical data. As indicated, in silica data predicted DCS class correctly in 74% of cases and HTS data in 81% of cases using rat in situ perfusion as the reference data set. In many cases, errors were associated with the misclassification of DCS Class I or III with class II or IV (permeability errors). Misclassifications based on solubility errors were less common. Also some very poorly soluble Class II compounds can masquerade as Class IV candidates based on precipitation and adsorption to the hlters and plastics associated with the permeability apparatus. 

According to this scheme 17) the polymeric cyanides belong either to class I or class II. The first group of cyanides mentioned above belongs to class I. The positions of the absorption bands of the pol3muclear compounds may be somewhat displaced compared with the spectra of the mononuclear species. No bands, however, are observed that cannot be attributed to one of the mononuclear chromophores. The electronic interaction between and M is assumed to be negligible, and the two valences are supposed to be firmly trapped. Accordingly, the deeply colored polynuclear cyanides may be considered as class II compounds. 

---