Nanoparticulate Drug Delivery Strategies to Address Intestinal Cytochrome P450 CYP3A4 Metabolism towards Personalized Medicine

Abstract

Drug dosing in clinical practice, which determines optimal efficacy, toxicity or ineffectiveness, is critical to patients’ outcomes. However, many orally administered therapeutic drugs are susceptible to biotransformation by a group of important oxidative enzymes, known as cytochrome P450s (CYPs). In particular, CYP3A4 is a low specificity isoenzyme of the CYPs family, which contributes to the metabolism of approximately 50% of all marketed drugs. Induction or inhibition of CYP3A4 activity results in the varied oral bioavailability and unwanted drug-drug, drug-food, and drug-herb interactions. This review explores the need for addressing intestinal CYP3A4 metabolism and investigates the opportunities to incorporate lipid-based oral drug delivery to enable precise dosing. A variety of lipid- and lipid-polymer hybrid-nanoparticles are highlighted to improve drug bioavailability. These drug carriers are designed to target different intestinal regions, including (1) local saturation or inhibition of CYP3A4 activity at duodenum and proximal jejunum; (2) CYP3A4 bypass via lymphatic absorption; (3) pH-responsive drug release or vitamin-B12 targeted cellular uptake in the distal intestine. Exploitation of lipidic nanosystems not only revives drugs removed from clinical practice due to serious drug-drug interactions, but also provide alternative approaches to reduce pharmacokinetic variability.

The Promise of Nanotechnology in Personalized Medicine

“…The M cells are located in the Peyer’s patches and have a high inclination to transport and induce endocytosis of antigens into these ones. Strategies that target the M cells include the mimicking of the entry of pathogens such as Salmonella and Yersinia or the targeting of specific receptors such as the integrins that are located on the surface of these cells [ 64 ].…”

“…The distal jejunum and ileum are regions in which the CYP3A4 expression and activity are lower than that present in the proximal gastrointestinal tract. As the pH of the jejunum and ileum is near 7 and 8, respectively, the use of pH-sensitive nanoparticles could be useful to deliver a higher concentration of drugs in these regions, in order to over-saturate the CYP3A4 enzyme, and to have a greater number of drugs that are able to bypass the metabolism [ 64 ].…”

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…CYP3A4 and P‐gp are co‐expressed in the intestine, which can synergistically regulate intestinal transporters and drug metabolism; finally, limit the oral bioavailability of the drug because both have the almost same substrate specificity and may also be responsible for the drug–drug interaction (Zhang, Dong, et al, 2021; Sun et al, 2021; Schaffenburg et al, 2021; Thummel, 2007). The total amount of intestinal CYP3A4 content averages about 40% of the liver content.…”

In silico approach: Prediction of ADMET, molecular docking, and QSPR of secondary metabolites in Mangroves

“…The pharmacokinetic data in Table 2 revealed that emodin and dolichol-20 (C100) do not inhibit CYP3A4 enzymes, suggesting that it is safe to use emodin and dolichol-20 (C100) with a wide range of CYP3A4 substrates (including alprazolam, atorvastatin, vincristine, halothane, hydrocortisone, zidovudine, carbamazepine, codeine, cortisol, caffeine, lidocaine, lovastatin, midazolam, nifedipine, paracetamol, tacrolimus, tamoxifen, testosterone, phenytoin, cyclosporine, cyclophosphamide, erythromycin, R-warfarin, and S-warfarin). This is due to the fact that the isoenzyme type CYP3A4 is the primary metabolizer of approximately 75% of all medicines metabolized by CYP (Zhang et al, 2021). According to a prior study examining the 200 most widely prescribed medications in the United States, the CYP isoenzyme O n l i n e F i r s t type CYP3A4 metabolizes around 46% of pharmaceuticals (Sychev et al, 2018).…”

“…According to the energy principle, the lowest score was used since a molecule is most stable at the lowest energy level. As a result, it was worthwhile to test the actual binding affinities of these small molecules to the target protein to see if the computer predictions corresponded to the biological scenario (Widiyana, 2021;Zhang et al, 2021).…”