Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

Abstract

Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as dietary substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given dietary substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-dietary substance interactions appropriately.

Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma

“…Therefore, intestinal exposure to mitotane may lead to enzyme induction and metabolic transformation already during absorption. Inhibition of intestinal (and hepatic) CYP3A enzymes may therefore shorten the time interval to reach therapeutic serum levels of mitotane (44). There are already inhibitors of CYP3A4 used in the clinic like ritonavir or cobicistat, which are pharmacokinetic enhancers of protease inhibitors (45,46).…”

Human PXR-mediated induction of intestinal CYP3A4 attenuates 1α,25-dihydroxyvitamin D3 function in human colon adenocarcinoma LS180 cells

“…DHB is a major component of grapefruit juice and mediates the inactivation of intestinal CYP3A4 with periodic consumption of regular strength juice [42]. The dose of DHB (20 μM) in this study is comparable to the dietary level of normal strength grapefruit juice [42], which has been reported to efficiently inhibit the enteric CYP3A thereby altering bioavailability of CYP3A substrates; e.g. itraconazole [43], cyclosporine [44], tacrolimus [45], budesonide [46], oxycodone [47], and midazolam [48].…”

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

“…Metabolism-related fooddrug interactions are highly dependent on the composition of the food, namely, they are mostly associated with fruits, vegetables, alcoholic beverages, teas and herbs. For example, ingestion of grapefruit juice can enhance systemic exposure of a drug metabolized by CYP3A4 by 1400% [42]. Also, ingestion of carbohydrates can reduce the oxidation of drugs, such as antipyrine and theophylline [43].…”

“…Also, ingestion of carbohydrates can reduce the oxidation of drugs, such as antipyrine and theophylline [43]. Also, ingestion of grapefruit juice can enhance systemic exposure of a drug metabolized by CYP3A4 by 1400% [42]. The gastrointestinal effects due to a fasted or fed system should be investigated considering the potential effect on the pharmacokinetic properties of a drug.…”