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.
Highlights
Failed drug therapy due to unintended drug-drug interactions occurs widely in clinical medicine and could impact drug efficacy and safety [1,2,3]
In order to exert a therapeutic effect, drugs must be absorbed via a certain route of administration, such as oral, intravenous, intramuscular, nasal and subcutaneous, among which oral delivery is the most preferred method due to several well-recognized reasons, including convenience, non-invasiveness, extended drug release, suitability for long-acting medication and a long shelf-life [5,6], but the liver and small intestine constitute the main sites of drug metabolism, leading to pharmacokinetic (PK) variability [7,8]
We explore the essentiality of overcoming intestinal CYP3A4 as a critical physiological barrier in the gastrointestinal tract (GIT)
Summary
Failed drug therapy due to unintended drug-drug interactions occurs widely in clinical medicine and could impact drug efficacy and safety [1,2,3]. Neoral fatty was acids) much are lessknown influenced by fatgested dietary The U.S Food and Drug Adminaccount for approximately 2–4% of the pharmaceutical market, represent one of the most istration (FDA) has issued guidance for “Food-Effect Bioavailability and Fed Bioequivapopular approaches to improve the solubilization of poorly water-soluble compounds lence Studies” to label some medications that are strongly influenced by a meal [24]. Process (e.g., bile salts) of ingested lipids from formulations forms solubilised phases to The influence of those physiological GIT barriers (e.g., CYP3A4, pH) as well as exfacilitate the drug absorption [30,31]. With the aid of computer modeling and advanced microand nanotechnologies, LNS with controlled drug release kinetics may potentially tackle in vivo variability of CYP3A4 susceptible drugs with a narrow therapeutic index
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