Abstract
The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and physiological factors (e.g., metabolism and transport across the gastrointestinal tract). The aim of this work was to investigate the effect of food on the high-affinity intestinal efflux transporter substrate drugs. We hypothesized that transport efficiency is higher in the fed state as compared to the fasted state because of the lower intestinal lumen drug concentration due to prolonged gastric emptying time. A systematic analysis of reported clinical food-effect (FE) studies on 311 drugs was performed and the association of the efflux transport efficiency was investigated on the FE magnitude, i.e., changes in maximal plasma concentration and area under the plasma concentration–time profile curve for both solubility and permeability-limited drugs. In total, 124 and 88 drugs showed positive and negative FE, respectively, whereas 99 showed no FE. As expected, the solubility-limited drugs showed positive FE, but interestingly, drugs with a high potential for efflux transport, were associated with negative FE. Moreover, a high-fat diet was associated with a higher magnitude of negative FE for high-affinity efflux transporter substrates as compared to a low-fat diet. To account for changes in drug absorption after food intake, the prolonged gastric emptying time should be considered in the physiologically based pharmacokinetic (PBPK) modeling of orally absorbed efflux transporter substrate drugs.
Highlights
85% of the top 200 prescription drugs are administered orally [1], high variability in oral drug pharmacokinetics (PK) is associated with a risk of toxicity or lack of efficacy for narrow-therapeutic index drugs [2]
This study confirmed that drugs with a higher dose number are prone to positive
High-affinity efflux transport substrate drugs exhibit a higher likelihood of negative FE that is not predictable by a dissolution test
Summary
85% of the top 200 prescription drugs are administered orally [1], high variability in oral drug pharmacokinetics (PK) is associated with a risk of toxicity or lack of efficacy for narrow-therapeutic index drugs [2]. Oral drug absorption is influenced by multiple extrinsic and intrinsic factors that can alter systemic drug exposure [3,4]. Food is one of the major extrinsic factors that affects the absorption of oral drugs including narrow therapeutic index drugs such as amiodarone [5], phenytoin [6], rifampicin [7], and tacrolimus [8]. Food can influence several drug properties, including dissolution rate, ionization state, complexation, and chemical stability [2]. The impact of the complex interplay of altered drug properties and physiological factors on drug absorption in the fed versus the fasted state is not well characterized
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