Ionization oral bioavailability

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. 

Few pharmacokinetic studies are carried out beyond the range of 28-40 years and, consequently, there are few data on oral bioavailability for extremes of age. Gastric fluid is less acidic in newborns than in adults, which can affect the absorption of ionizable and acid-labile drags. Neonates are also associated with a leaky epithelium, which permits the absorption of proteins and other macromolecules not normally absorbed from the GI tract. Decreased enzymatic activity, including hepatic first-pass metabolism, is associated with the elderly, which may result in an increased oral bioavailabiliy for drags subject to the first-pass effect. 

Ionization, pKa, and Aqueous Solubility Most drugs are weak acids or bases. It is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. Since drugs must be in solution before they can be absorbed, compounds with very low aqueous solubility usually have the oral bioavailability problems because of limited GI transit time of the undissolved drug particles and they are limited at the absorption site. Unfortunately, for many of the drugs and bioactive compounds, the site of maximum absorption occurs at the site where solubility of these compounds is least. 

The ion pairing approach involves coadministration of a hydrophilic or polar drug with a suitable lipophilic counterion, which consequently improves the partitioning of the resultant ion pair (relatively more lipophilic) into the intestinal membrane. In fact, the approach seems to increase the oral bioavailability of ionizable drugs, such as atenolol, by approximately 2-fold.However, it is important that a counterion possess high lipophilicity, sufficient aqueous solubility, physiological compatibility, and metabolic stability. Some of the successful applications of this approach have already been described in previous reviews " and therefore, will not be described any further here. 

Elixirs are sweetened hydroalcoholic oral solutions that are specially formulated for oral use in infants and children. Digoxin, a non-ionizable cardiotonic glycoside, is practically insoluble in water and is solubilized in propylene glycol, 10% ethanol, flavor, sweetener, preservative, and buffers to 50pg/ml in Lanoxin Elixir Pediatric from which the oral bioavailability of digoxin is 70-85%. Phenobarbital, an anticonvulsant and sedative with an intrinsic water solubility of 1 mg/ml, is solubilized in water, 23% ethanol, glucose, sodium saccharin, and flavors to 3.5 mg/ml in Donnatal Elixir. 

Sirolimus is a non-ionizable and water-insoluble immunosuppressant that is formulated in Rapamune as a 1 mg/mL solution in polysorbate 80 and the proprietary excipient combination, Phosal 50 PG , which is composed of phosphatidylcholine, propylene glycol, mono- and diglycerides, 1.5-2.5% ethanol, soy fatty acids and ascorbyl pahnitate. The oral bioavailability of... 

Despite excellent IV activity, enalaprilat has very poor oral bioavailability. Esterification of enalaprilat produced enalapril (Fig. 28.9), a compound with superior oral bioavailability. The combination of structural features in enalaprilat, especially the two carboxylate groups and the secondary amine, are responsible for its overall low lipophilicity and poor oral bioavailability. Zwitterion formation also has been suggested to contribute to the low oral activity (25), and a comparison of the pKa values for the secondary amine of enalaprilat and enalapril supports this explanation. Ionization of the adjacent carboxylate in enalaprilat greatly enhances the basicity of the secondary amine such that the pKa of the amine in this compound is 8.02, whereas in enalapril, it is only 5.49. Thus, in the small intestine, the amine in enalaprilat will be primarily ionized and form a zwitterion with the adjacent carboxylate, but the amine in enalapril will be primarily un-ionized (26). 

Prochlorperazine fulfils the criteria for efficient transmucosal delivery it is a highly lipid soluble base with a pKa of 8.1 and is therefore largely non-ionized at salivary pH. Because first-pass metabolism is avoided, the bioavailability via the buccal route is much higher than via the oral route (Figure 7.2). 

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