CYP3A4 substrates

Ekins S, Bravi G, Wikel JH, Wrighton SA. Three dimensional quantitative structure activity relationship (3D-QSAR) analysis of CYP3A4 substrates. J Pharmacol Exp Ther 1999 291 424-33. 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Quetiapine 3A4 2D6, 2C9 Carbamazepine and phenytoin topiramate prednisolone. Fluvoxamine fluoxetine sertraline (high dose) CYP3A4 substrates grapefruit juice. 

P Schmeidlin-Ren, DJ Edwards, ME Fitzsimmons, K He, KS Lown, PM Woster, A Rahman, KE Thummel, JM Fisher, PF Hollenberg, PB Watkins. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos 25 1228-1233, 1997. 

The metabolism of several CYP3A4 substrates in microsomes from the upper small intestine has been compared with liver microsomal metabolism. The results are summarized in Table 13.3. Thus, microsomes from the human upper small intestine can metabolize CYP3A4 substrates at rates approaching those found in human liver microsomes. However, the rate of metabolism in intestinal microsomes can be highly variable (8-fold for sirolimus [17] and 18- to 29-fold for midazolam [19]). 

K. S., Woster, P. M., Rahman, A., Thummei, K. E., Fisher, J., Hollenberg, P. F., Watkins, P. B., Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit juice constituents, Drug Metab. Disp. 1997, 25, 1228-1233. 

Cruciani et al. [92] have developed the program Metasite for the prediction of the site of oxidative metabolism by CYP450 enzymes. Metasite uses GRID molecular interaction fields to fingerprint both structures of CYP450s (from homology models or crystal structures) and test substrates and then matches the fields. Zhou et al. [93] showed that Metasite was able to correctly predict the site(s) of metabolism 78% of the time for 227 CYP3A4 substrates. Caron et al. [94] used Metasite to predict the oxidative metabolism of seven statins. 

FIGURE 4.19 Structures of the CYP3A4 substrates, metyrapone and progesterone. 

Figure 7.5 Mucosal-to-submucosal (m-s), Tapp values across human buccal culture of midazolam (CYP3A4 substrate), bufuralol (CYP2D6 substrate), tolbutamide (CYP2C9 substrate), and the nonmetabolized, high-permeability control compound caffeine (average SEM, N = 1 — 3 replicates). (Asterisk) in the presence of CYP inhibitors (CYP3A4-ketoconazole CYP2D6-quinidine CYP2C9-suphaphenazole). In all treatments integrity of the culture was verified by permeation of Lucifer yellow (< 2.0 x 10-6 cm/s). Results from internal study by Absorption Systems Company.

The predominant interaction of CYP3A4 is via hydrophobic forces and the overall lowering of lipophilicity can reduce metabolic lability to the enzyme. Figure 7.14 shows the relationship between unboimd intrinsic clearance in man and lipophilicity for a variety of CYP3A4 substrates. The substrates are cleared by a variety of metabolic routes including N-dealkylation, aromatization and aromatic and aliphatic hydroxylation. The trend for lower metabolic lability with lower lipophilicity is maintained regardless of structure or metabolic route. 

Fig. 7.14 Unbound intrinsic clearance of CYP3A4 substrates and relationship with lipophilic-ity. The data has been calculated from various clinical studies with the drugs listed in order of decreasing lipophilicity. 

Diltiazem and verapamil inhibit other CYP3A4 substrates, whereas the dihydropyridines do not. 

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

Metabolism/Excretion-Trazodone is extensively metabolized in the liver and is a CYP3A4 substrate. Elimination is biphasic, with a half-life of 3 to 6 hours and 5 to 9 hours, respectively, and is unaffected by food. 

Domanski, T. L., He, Y. A., Khan, K. K., Roussel, F., Wang, Q., and Halpert, J. R. (2001) Phenylalanine and tryptophan scanning mutagenesis of CYP3A4 substrate recognition site residues and effect on substrate oxidation and coop-erativity. Biochemistry 40, 10,150-10,160. 

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