Oral Bioavailability Assessment by Ayman F. El-Kattan & Mike S. Lee

Author:Ayman F. El-Kattan & Mike S. Lee
Language: eng
Format: epub
ISBN: 9781118916933
Publisher: John Wiley & Sons, Inc.
Published: 2017-06-12T00:00:00+00:00

Figure 6.6 The Cmax and AUC of talinololfollowing single doses of 100-mg talinolol immediate-release, 100-mg talinolol controlled-release.

Tubic et al. 2006 [200]. Reproduced with permission of Elsevier.

Compounds can also be classified in reference to their P-gp activity into high, low, or nonresponders (Table 6.3) [201–204]. For high responders, intestinal absorption is significantly impacted by interindividual differences in P-gp expression levels or by coadministration of P-gp substrates/inhibitors. On the other hand, the impact of changes in P-gp function on the oral absorption of low responders is limited [153]. High responders typically belong to BDDCS Class 3 (fexofenadine and digoxin) or BDDCS Class 4 (paclitaxel). Consistent with their classification, these molecules have inherent low intestinal permeability, which is in part attributed to P-gp-mediated efflux. Coadministration of fexofenadine and ketoconazole was associated with an increase in fexofenadine Cmax and area under plasma concentration–time curve (AUC) with no change in half-life. This suggests the inhibition of P-gp-mediated efflux along the GIT, since fexofenadine is not subjected to any metabolism [205]. Similar trend of increase in the oral bioavailability of digoxin and paclitaxel was reported with coadministration with P-gp inhibitors [206, 207]. In vivo absorption of low responders indinavir, sulindac, and ranitidine have minimal efflux activity due to substrate recognition, while incomplete absorption of nonresponders is attributable to their intrinsic solubility and permeability limitations and P-gp has no significance. Overall, P-gp activity may play a significant role in limiting intestinal permeability of BDDCS Class 2–4 P-gp substrates based on their efflux activity, but not for BDDCS Class 1 compounds irrespective of P-gp activity. It should be emphasized that compounds that have high intestinal permeability are predominantly absorbed in the jejunum that has short transit time (∼40 min) and lower P-gp expression. Therefore, P-gp-mediated efflux has limited impact on the absorption of these molecules (BDDCS Class 1). However, the intestinal absorption of compounds with limited solubility/permeability (BDDCS Classes 2–4) is shifted to the ileum that has higher P-gp expression and an intestinal transit time of ∼140 min [208]. Overall, these molecules make the moderately absorbed P-gp substrates more susceptible to P-gp-mediated efflux (BDDCS Classes 3–4) (Figure 6.7).

Table 6.3 Classification Scheme of the Drugs Based on the Relevance of P-gp-Mediated Efflux Transport on the Intestinal Drug Absorption In Vivo [201–203]

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