Cytochrome P450 3A4 CYP3A4

In the past, it was always assumed that the liver, rather than the intestine was the main guardian of the systemic circulation and that metabolism of xenobiotic compounds by the gut was functionally not so important. Although the importance of hepatic metabolism cannot be overstated, there is overwhelming evidence that the intestinal barrier provided by CYP3A4 is a major determinant of systemic bioavailability of orally administered drugs70, for example, intestinal metabolism may account for as much as 50% of oral cyclosporine metabolism71. The cytochrome appears to be identical to that in hepatic cells and produces a similar pattern of Phase 1 metabolites72.

It appears that CYP3A4 and P-glycoprotein are functionally integrated as there is a great overlap between the substrates for both systems. Secondly, the two complexes are co-localised in tips of the villus and not present in the crypts, and finally the CYP3A4 and P-glycoprotein genes appear to be close to each other on the same chromosome (Figure 6.13)72.

The inter-relationship of P-glycoprotein and CYP3 A4 operates in a complex manner. Firstly, P-glycoprotein limits the total drug transport across the membrane so that CYP3A4 in the enterocytes is not saturated. Secondly, the slowing of drug absorption by P-glycoprotein increases the duration of exposure of the drug to the CYP3 A4 in the enterocyte, thus providing greater opportunity for metabolism. In addition, the metabolites generated by CYP3A4 are substrates for it. These metabolites are actively transported out of the cell by P-glycoprotein so that they do not compete with the metabolism of the parent drug.

Intestinal Lumen Enterocyle Blood

Intestinal Lumen Enterocyle Blood

Figure 6.13 Probable mechanism of interaction of P-glycoprotein and cytochrome

P4503A4 (CYP3A4)

Figure 6.13 Probable mechanism of interaction of P-glycoprotein and cytochrome

P4503A4 (CYP3A4)

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