Physiological Pharmaceutics

Small intestine 131It was soon realised that the wide diversity of compounds transported were mutualinhibitors, i.e. these compounds were also substrates for P-glycoprotein. Several of thesereversal agents are now under trial in the treatment of acute myeloid leukaemia.There is some speculation that P-glycoprotein may not prevent the completeabsorption of a substrate but may simply control entry at a rate sufficient to ensure intestinalmetabolism. The evidence for this is that the P-glycoprotein action appears to work inconcert with cytochrome P450 3A4.Cytochrome P450 3A4 (CYP3A4)In the past, it was always assumed that the liver, rather than the intestine was the mainguardian of the systemic circulation and that metabolism of xenobiotic compounds by thegut was functionally not so important. Although the importance of hepatic metabolismcannot be overstated, there is overwhelming evidence that the intestinal barrier provided byCYP3A4 is a major determinant of systemic bioavailability of orally administered drugs 70 ,for example, intestinal metabolism may account for as much as 50% of oral cyclosporinemetabolism 71 . The cytochrome appears to be identical to that in hepatic cells and producesa similar pattern of Phase 1 metabolites 72 .It appears that CYP3A4 and P-glycoprotein are functionally integrated as there is agreat overlap between the substrates for both systems. Secondly, the two complexes are colocalisedin 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 (Figure6.13) 72 .The inter-relationship of P-glycoprotein and CYP3 A4 operates in a complexmanner. Firstly, P-glycoprotein limits the total drug transport across the membrane so thatCYP3A4 in the enterocytes is not saturated. Secondly, the slowing of drug absorption byP-glycoprotein increases the duration of exposure of the drug to the CYP3 A4 in theenterocyte, thus providing greater opportunity for metabolism. In addition, themetabolites generated by CYP3A4 are substrates for it. These metabolites are activelytransported out of the cell by P-glycoprotein so that they do not compete with themetabolism of the parent drug.Figure 6.13 Probable mechanism of interaction of P-glycoprotein and cytochromeP4503A4 (CYP3A4)