Intestinal metabolism inhibition

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Until recently, intestinal metabolism via CYP3A4-mediated metabolic pathways was thought to be insignificant because of the lower levels of expression compared with that seen in the liver and slower metabolic rates measured for intestinal microsomes (224). However, similar Km values have been reported for midazolam 1 -hydroxylation by microsomes obtained in the upper intestine and the liver (254,255). This correlation indicates that the upper intestine and hepatic CYP3 A4 are functionally equivalent. Such findings further establish the importance of the intestine in the elimination of orally administered substrates for CYP3 A4-mediated metabolic pathways. Additionally, coadministration of substrates/inhibitors that may alter the function of these proteins (induction, inhibition) could further be responsible for the variability in intestinal absorption (dmg interactions) seen for some dmgs. 

Figure 3 Simulation of the effect of enzyme inhibition on oral midazolam AUC. Hepatic extraction in the absence of an inhibitor was set at 0.44. The initial intestinal extraction was varied from 0.0 to 0.9. The inhibitor/ ratio was assumed to be equivalent for inhibition of hepatic and intestinal metabolism (i.e., 7U = 7gm). Mucosal and hepatic plasma flows were assumed to be 240 and 780 mL/min. Simulations were obtained from Eq. (8), assuming an initial intestinal extraction ratio of 0.00,0.27, 0.43,0.60,0.78, and 0.88.

Dietary habits can influence the TK and toxicity of solvents in several ways. The mere bulk of food in the stomach and intestine can inhibit systemic absorption of VOCs. Solvents in the GI tract partition into dietary lipids, largely remaining there until the lipids are emulsified and digested. This substantially delays the absorption of VOCs such as CCI4 and its hepatotoxicity. Increased incidences of cancer have been observed in obese humans possibly due to increase in liver CYP2E1 by ketone body formation. Caloric restriction has clearly been shown to reduce the incidence of cancer. Fasting results in increased P450 activities and reduced GSH, which affect the TK and toxicity of VOCs. Food may contain certain natural constituents, pesticides, and other chemicals, which may enhance or reduce the solvent metabolism. 

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

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