Oral bioavailability examples

Many street drugs are not administered in pill form because they have poor oral bioavailability. Examples include cocaine (3.12), heroin (3.13), and marijuana (active component, A10-tetrahydrocannabinol [3.14]) (Figure 3.9). Many legal prescription drugs also cannot be taken in oral form. Perhaps the most widely used injectable drug is insulin, a 51-peptide hormone that is rapidly broken down in the stomach when taken orally. 

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. 

The midazolam example shows that gut wall cytochrome P450 can contribute significantly to the attenuation of oral bioavailability of substrate drugs. In addition, the variability and site dependence of expression of the major intestinal CYPs can lead to significant effects on the disposition of orally delivered drugs. 

Some drugs with low intrinsic permeability achieve acceptable oral bioavailability because they are substrates for uptake transporters, which normally function in nutrient uptake. The most prominent example is the peptide transporter, PepTl, which is active toward peptidomimetic antibiotics such as cephalexin, the antiviral agent valacyclovir [24] and other drugs. PepTl is natively expressed in Caco-2 cells, and adenovirus transduction has been used to increase PepTl expression levels [25]. However, the expression of PepTl was not polarized in this system and this expressed system appears to be of limited value as an improved screening model. PepTl has also been expressed in Chinese hamster ovary cells and a variety of other mammalian systems [26, 27]. 

In a series of reports on their class of DPPIV inhibitors [27-29], workers from Merck have shown that the incorporation of an acid moiety (or related bioisostere) into an amine-containing template to furnish a zwitterionic system has been ofuse in minimizing hERG activity. For example, incorporation of an acid bioisostere into the biaryl P-methylphenylalanine template has been shown to afford enhancements in selectivity over hERG (cf. compounds 40 and 41) [29]. A concomitant reduction in oral bioavailability was observed between the two compounds, which underlines the main limitation in this approach. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

A few interesting glyceride prodrugs of peptides can be found in the literature. For example, the pentapeptide renin inhibitor isovaleryl-Phe-Nle-Sta-Ala-Sta was derivatized to the l,3-dipalmitoyl-2-glyceryl ester (8.40) in the hope of improving oral bioavailability [55]. The in vitro results were... 

The highly polar clodronic acid (9.53, R, R = Cl), etidronic acid (9.53, R = Me, R = OH), and a number of analogues have demonstrated their clinical value in the treatment of osteoporosis, but they must often be administered by slow intravenous infusion due to their poor oral bioavailability. Esterification to orally available prodrugs is, thus, an actively investigated strategy. Promising results have, for example, been obtained with (pivaloyl-oxy)methyl esters of clodronic acid [120]. 

Conversion of the type B hydroxamic acids to hydroxyureas led to further enhancements of oral bioavailability and in vivo potency. Abbott s (133) [316,317] and BW-B70C (135) from Burroughs Wellcome [315,318] are examples. A direct comparison of the type B hydroxamic acid (134) and the hydroxyurea (133), as well as the type A and type B compounds (126) and (128), is shown in Table 1.1 [304,316]. Methylation on the A -position of the... 

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