Solubility oral bioavailability

In addition, most of the SOSA-generated leads satisfy Lipinski [47], Veber [48], Bergstrom [49], and Wenlock s [50] recommendations in terms of solubility, oral bioavailability, and drug-likeness. 

As mentioned in Sect. 3, it is important to establish a detailed lead profile at the beginning of a lead identification effort. Criteria vary in different lead identification or hit-to-lead groups, but generally include some or all of the following potency, functional activity, selectivity, MW, clogP, solubility, permeability, microsomal stability and/or hepatocyte clearance, and preliminary PK including oral bioavail-ability. An example of a lead profile for a kinase inhibitor project is illustrated in Table 1 [21],... 

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

Above 5 Low solubility and poor oral bioavailability. Erratic absorption. High metabolic liability, although potency may still be high. Basic amines tend to show high to very high Vd (Volume of distribution = ratio of overall tissue binding to plasma protein binding)... 

BCS Class IV Low-solubility, low-permeability drugs. These compounds have very poor oral bioavailability. They are not only difficult to dissolve but often exhibit limited permeability across the GI mucosa. These drugs tend to be very difficult to formulate and can exhibit very large intersubject and intrasubject variability. 

HU, a freely water-soluble molecule, crosses the intestinal wall and other cells by passive diffusion [5, 6], and tissue concentration of HU rapidly matches its blood concentration [7]. The oral bioavailability of HU is nearly complete and hence therapeutically simple to administrate. HU undergoes biotransformation and is converted into urea by a yet-to-be identified hepatic P450 monooxygenase (CYP) enzyme [8, 9], Elimination of HU and its metabolites involves both renal and non-renal mechanisms. 

Other possibilities for insoluble materials are to mix the desired amount of material with a small amount of the animal s diet or to use capsules. The difficulty with the diet approach is the likelihood that the animal will not consume all of the treated diet or that it may selectively not consume chunks of test material. Use of capsules, meanwhile, is labor intensive. In rare cases, if all of these approaches fail, it may not be possible to test a material by oral administration. In capsules, particle size is generally inversely related to solubility and bioavailability. However, milling of solids may adversely affect their chemical nature and/or pose issues of safety. 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

Single Test Compound Clustering with Several Marketed Drugs on the Basis of the Similarity of In Vitro Profile Results Including Human Absorption, Oral Bioavailability, Permeability, Solubility, Log D, and Metabolic Stability Characteristics... 

Compound Solubility (gM) Log D Apparent Permeability (10-6 cm/sec) Metabolic Stability (% Remaining) Oral Bioavailability (%) Absorption (%)... 

The oral bioavailability of hypericum may be altered and improved by a combination of its constituents. A hypericum extract containing naphthodianthrones is inactive in a water suspension, but very effective when another constituent, procyanidin, is present. Procyanidin had the effect of increasing the water solubility of naphthodianthrones, and thus increasing their pharmacokinetic availability (Butterweck et ai. 1997). Further, the facilitative effect of procyanidin exhibited an inverted U curve. 

Compounds with low solubility and high permeability (BCS Class II [15]). For these compounds, oral bioavailability may be limited by solubility, and significant formulation efforts may be required before acceptable properties are obtained. 

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