Non-metabolic Barriers to Oral Absorption

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. 

More recently, P-gp has been shown to be expressed in normal human tissues. In the gut, the expression is highly localized to the apical surfaces of the gut wall epithelium [30], where it is well placed to intercept its substrates and deposit them back into the lumen of the gut in a counter-absorptive manner. 

Wacher et al. [31] have shown that, in contrast to CYP3A4, P-gp mRNA levels increase longitudinally along the intestine (lowest levels in the stomach and highest in the colon). Lown et al. [32] have shown using duodenal mucosal biopsies (n = 20) that there was a 10-fold variation in the P-gp mRNA level, suggesting that there will be variability in the expression of P-gp in the gut and this will lead to potential variability in oral bioavailability. 

The introduction of P-gp knockout mice [38] has enabled workers to study the role of P-gp in limiting the oral bioavailability of its substrates. An example of this is the NK2 antagonist, UK-224,671 [39, 40] (Fig. 13.4). 

In man, the oral bioavailability of UK-224,671 is less than 10% [39]. Since clearance of UK-224,671 is low relative to liver blood flow, the poor oral bioavailability is due to incomplete absorption of the compound from the GIT. Caco-2 flux experi- 

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