Metabolism gut wall

Poorly absorbed compounds have been identified as those with a PSA > 140 A2, but considerably more scatter was found around the sigmoidal curve observed for a smaller set of compounds [78]. This is partly due to the fact that many compounds do not show only simple passive diffusion, but are also affected by active carriers, efflux mechanisms involving P-glycoprotein (P-gp) and other transporter proteins, as well as gut wall metabolism. A further refinement in the PSA approach is expected to come from taking into account the strength of the hydrogen bonds, which in principle already is the basis of the HYBOT approach described below. 

A direct in vivo assessment of the quantitative importance of gut wall metabolism and transport of drugs and metabolites in humans is difficult and consequently has been attempted only rarely [3, 6, 11, 12, 15, 16, 23, 25-32, 34, 35, 81]. The most direct in vivo approach to investigating these processes in drugs with variable and incomplete bioavailability was intestinal perfusion by single-pass per-... 

I 73 The Importance of Gut Wall Metabolism in Determining Drug Bioavailability... 

The expression of a significant gut wall first-pass extraction ratio has several implications for affected drugs. First, oral bioavailability is lower than would be expected from the extent of absorption and the hepatic first-pass extraction. Second, the variability in expression of gut wall metabolic enzymes and transporters can lead to significant variability in gut wall first-pass extraction and thus oral bioavailability. Finally, the site of expression of these enzymes and transporters (i.e., the villus tip) brings them into contact with potentially co-administered drugs or dietary constituents, which could be inhibitors or inducers. Thus, there is the potential for drug-drug interactions at the level of the gut wall. 

This chapter has provided only a short review of a very large subject, and for further details the reader is directed to excellent reviews on gut wall metabolism [62], transporter proteins [63], and cytochromes P450 [11]. 

The volume is divided into five sections. Part one looks at the experimental study of membrane permeability and oral absorption. In Part two, problems of measuring and prediction solubility, as one of the key determinants in the absorption process, will be discussed in detail. In the next part, progress in the science around transporter proteins and gut wall metabolism and their effect on the overall absorption process is presented. Part four looks at the in silico approaches and models to predict permeability, absorption and bioavailability. In the last part of the book, a number of drug development issues will be highlighted, which could have an important impact of the overall delivery strategies for oral pharmaceutical products. 

The loss of that portion of the dose that is not bioavailable. This would include, among others, loss through intestinal and gut-wall metabolism, lack of absorption, and first-pass hepatic metabolism. 

Fromm MF, Dilger K, Busse D, Kroemer HK, Eichelbaum M, Klotz U. Gut wall metabolism of verapamil in older people effects of rifampicin-mediated enzyme induction. Br J Clin Pharmacol 1998 45(3) 247-255. 

Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism. Drug Metab Dispos 1996 24(10) 1121-1123. 

Back DJ, Breckenridge AM, Maciver M, et al. The gut wall metabolism of ethinyloestradiol and its contribution to the pre-systemic metabolism of ethinyloestradiol in humans. Br J Clin Pharmacol 1982 13(3) 325-330. 

Glaeser H, Drescher S, Hofmann U, et al. Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans. Clin Pharmacol Ther 2004 76(3) 230-238. 

In an intestinal perfusion study of the effect of ketoconazole 40 pg/ml on the jejunal permeability and first-pass metabolism of (R)- and (5)-verapamil 120 pg/ml in six healthy volunteers, ketoconazole did not alter the jejunal permeability of the isomers, suggesting that it had no effect on the P-glycoprotein mediated efflux. However, the rate of absorption increased, suggesting inhibition by ketoconazole of the gut wall metabolism of (i /5)-verapamil by CYP3A4 (35). 

To assess the impact of drug metabolism in the gut wall on oral bioavailability and develop adequate models for gut wall metabolism, it is necessary to understand the physiology of the intestinal mucosa. 

The obvious clinical limitations in directly assessing gut wall metabolism in humans underline the importance of modeling approaches. These will be briefly reviewed in Section 12.4.3. 

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