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

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.