Class I compound

In class I compounds (or complexes) the two sites are very different from each other and the valences are strongly localized. The properties of the complex are the sum of the properties of the constituting ions. The optical MMCT transitions are at high energy. The compounds are insulators. Here are some examples [60, 97]. In GaCl2, or Ga(I)[Ga(III)Cl4] there are dodecahedrally coordinated Ga(I) ions with Ga-Cl distances of 3.2-3.3 A and tetrahedrally coordinated Ga(III) ions with Ga-Cl distance 2.2 A. In [Co(III)(NH3)6]2- Co(II)Cl4)3 there are low-spin, octahedrally coordinated Co(III) ions and high-spin, tetrahedrally coordinated Co(II) ions. For our purpose this class is not the most interesting one. 

Class I compounds have both good solubility and permeability and generally offer no problems with regard to having a good absorption profile (e.g., acetaminophen, disopyramide, ketoprofen, metoprolol, nonsteroidal anti-inflammatory agents, valproic acid, verapamil). In general, one would not expect the presence of food to influence the absorption of this class... 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

Nitroaniline remains a Class I compound over the whole gamut of solvents, but crossover between the different types may be observed with molecules closer to either end of the cyanine range (Class II). Crossover will... 

All chemicals tested were classified according to the scheme shewn in Table l. Class I compounds are inactive while Class II materials are good toxicants but do not have the required delayed toxicity. Class III compounds have delayed action, but the concentration range of their activity is too narrow. The type of activity we are looking for in a toxicant is exemplified by a Class IV or V response, i.e., it exhibits delayed toxicity over a wide range of concentrations. 

Figure 1. Biopharmaceutical Classification System and Development Classification System. Class I compounds are defined as soluble and permeable through the gastrointestinal tract, Class II as poorly soluble but permeable through the GI tract, Class III as soluble but poorly permeable and Class IV as both poorly soluble and permeable. The further classification of Class II and III (simple and complex) is intended to provide additional data on the develop-ability of the drug candidate.

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). 

Compounds belongingto Class I are highly soluble and permeable. When formulated in an immediate-release dosage form, a Class I compound should rapidly dissolve and be well absorbed across the gut wall. However, absorption problems may still occur if the compound is unstable, forms an insoluble complex in the lumen, undergoes presystematic metabolism, or is actively secreted from the gut wall. Potential formulation strategies that may overcome such absorption barriers are discussed later in further detail. 

Dose dumping of Class I compounds, in particular, may cause more safety concerns than... 

The interrelationship between A0bs, K%, and the ratio kmlkout for class-I compounds is derived by replacing reaction (48) by reaction (56). 

The replacement leads to Equation (57) which substitutes Equation 50 for class-I compounds. 

The effect of k JkOM on the dynamics of pulse protonation of class-I indicator is depicted in Figure 39. A low ratio implies that the In(c) population is small, and there will be no apparent difference between Ks and Kobs (see Equation 57), which is the case for Neutral Red. In such cases, there will be no kinetic abberrations due to the interphase transition. As the ratio km/kOM increases, the contribution of In(c) population will increase, affecting all measured macroscopic parameters. At a very high ratio, the In(s) population is becoming so small that the pulse protonation will decline to nearly unobservable magnitude. This is the most profound distinction between the dynamic properties of two classes. Class-I I compounds will participate in pulse protonation whatever the kiJkout ratio, as their proton acceptor form is located in the proton-permeable phase. On the other hand, class-I compounds may be totally masked in pulse experiment due to depletion of the basic form from the (s) phase. 

Figure 39. The dependence of the macroscopic parameters of the protonation cycle of class-I compounds on kinlkom. The parameters were calculated from simulated dynamics run at the experimental conditions and rate constant of Neutral Red and listed in Figure 32. The values koul and pKs were arbitrarily set as 200 sec-1 and 5.5, respectively. (Top) The...

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