Intrinsic clearance intestinal

Decrease in intestinal wail intrinsic clearance (CLinl Q)... 

The process is a bit more complicated for orally administered CYP3A-cleared compounds because a portion of the DDI can occur in the inteshne during the first pass. The principles described above are the same, except that (i) the value of/cL term for the intestine can essenhally be assumed as unity and (ii) the value of [I]j nvo for the perpetrator is higher than that used for liver. Importanhy, the extent to which the new compound is extracted by the intestine, which is a function of the intrinsic clearance (CLim) of the new compound by CYP3A4, plays a major role in the potential magnitude of the DDI. High CL t compounds can be subject to greater DDI [103]. 

Figure 2 Simulation of the effect of enzyme induction on oral midazolam AUC. Hepatic extraction in the absence of an inducer was set at 0.44. The initial intestinal extraction was varied from 0.0 to 0.9. The inducer was assumed to cause an equivalent change in hepatic and intestinal intrinsic clearance. Mucosal and hepatic plasma flows were assumed to be 240 and 780 mL/min. Simulations were obtained from Eq. (6), assuming an initial intestinal extraction ratio of 0.00, 0.07, 0.27, 0.43, 0.60, and 0.88.

If we now turn to inhibitory interactions, fourfold reductions in hepatic and intestinal intrinsic clearance may cause up to a 16-fold increase in systemic AUC... 

Note that the effect of the inhibitor in the liver is independent of blood flow. This is not the case for the intestine, where the relative magnitude of mucosal blood flow compared with the baseline mucosal intrinsic clearance and the apparent intrinsic clearance in the presence of inhibitor must be considered. When the baseline mucosal intestinal intrinsic clearance is negligible compared to mucosal blood flow (i.e., negligible mucosal extraction), Eq. (11) will collapse into a much simpler and better recognized equation for a hepatic inhibitory interaction (3). 

If the CYP in gut contributes to the metaboKsm of a drug and is inhibited by a mechanism-based inhibitor, a change of bioavailability of the drug in gut should be taken into account. The ratio of Fgpj to Fg,ctr (the intestinal wall availability in the presence and absence of inhibitor) can be incorporated into the model (Equation 16.12). The ratio of Fg pq to Fg tr is estimated from the relative change in CLi ,g (gut intrinsic clearance) caused by the inhibitor (Equation 16.13). 

Oral bioavailability in vivo is dependent on both permeability and first pass metabolism that may occur in the intestine and liver. The intrinsic clearance per pmol CYP is assumed to be the same in human liver microsomes (HLM) as in intestinal microsomes (Yang et al. 2004), whereas CYP3A abundance represents the total amount of enzyme, 70,000 pmol in the gut (Paine et al. 1997). The abundance of CYP3A in the gut is calculated using (32). 

All orally administered chugs must pass through the gastrointestinal tract to reach the blood and thus pass the barrier formed by the enterocytes in the intestine. For years, low first-pass bioavailability of a drug was attributed mainly to clearance via hepatic metabolism and biliary clearance or incomplete absorption in the intestine due to poor solubility or intrinsic permeability properties. Although these are important factors in determining the overall oral bioavailability of certain... 

The gastrointestinal epithelium forms an extrinsic and an intrinsic barrier against diffusion of toxins and pathogens. The extrinsic barrier is characterized by secretion of mucus, which hinders colonization and accelerates clearance of pathogenic organisms. The importance of mucus as a barrier to drug absorption is discussed in Chapter 2 of this book. In addition, the intestinal immune... 

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