Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption

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Abstract

The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter–enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption/transport/elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs.

Introduction

Food–drug interactions have been widely associated with alterations of pharmacokinetic and pharmacodynamic parameters and proven to have significant clinical implications [1], [2]. The influence of concomitant food intake prompted the Food and Drug Administration (FDA) to issue a guidance for industry entitled, “Food-Effect Bioavailability and Fed Bioequivalence Studies” [3]. As a result, it is common to find medication labeling containing language denoting that maximum effect is achieved if the drug is administered with a meal. Conversely, some drug products show a decrease in the extent of availability and decreased efficacy with meal coadministration. Of course there are very many drugs for which food–drug interactions are non-existent or negligible.

The effect of food on the extent of availability is a significant concern during drug development. Ideally, it is most advantageous if a recommendation of oral drug administration can be provided independent of meal considerations. A food–drug interaction model would be beneficial in the early stages of development when preclinical predictions could be of particular use and service to the industry. Although various in vitro and in vivo models can be found [4], [5], [6], [7], to date no standard system exists to predict drug absorption and the effect of food.

The role of food, and its subsequent digestion, in oral drug absorption may be attributed to a myriad of variables ranging from the chemical characteristics of the drug itself to the postprandial changes in the gastrointestinal (GI) tract. Therefore, when attempting to predict variations in pharmacokinetics it is imperative to consider not only the physiochemical properties of the drug, but the GI luminal environment as well. In this review, we evaluate the GI luminal environment by taking into account the absorption/transport/elimination interplay and we evaluate the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. Here, we concentrate on combining these aspects into a comprehensive system to predict disposition and the role of food on drug absorption.

Section snippets

The BCS and the FDA

The oral absorption of a drug is fundamentally dependent on that drug's aqueous solubility and gastrointestinal permeability. Extensive research into these fundamental parameters by Amidon et al. [8] led to the Biopharmaceutics Classification System (BCS) that categorizes drugs into four groups, Class 1–Class 4 (Fig. 1). The BCS classifies compounds based on the critical components related to oral absorption. Centrally embracing permeability and solubility, the objective of the BCS is to allow

Oral absorption and the gastrointestinal tract

A majority of drugs marketed worldwide are administered orally. The efficacy of these drugs is dependent on the oral bioavailability, which in turn, is dependent on extent of absorption. Oral absorption, in basic terms, is dependent on the intestinal drug solubilization and the intestinal drug permeability. The amount of drug that goes into solution is affected by factors such as volume, pH, temperature and the compound's octanol/water partition coefficient, log Po/w. Thermodynamically, the

Fleisher et al. and the trends in the BCS

Fleisher et al. [14] documented several cases of food effects while taking into account the drug and its formulation classifications as established by the Biopharmaceutics Classification System (BCS) [9]. The review of Fleisher et al. [14] showed that in general high fat meals have no effect on the extent of oral drug availability for BCS Class 1 compounds, generally showed increased availability for Class 2 compounds, and generally showed decreased availability for Class 3 compounds. For

Juice/food/herbal extract effects

Considerable effort has been put into elucidating the effects of food on drug absorption and disposition. With very few exceptions, the mechanistic research representative of this effort has been retrospective in that first, an in vivo food effect is observed in a patient, followed by in vitro studies to the determine the cause of that effect. Such is the scenario that led to the discovery of grapefruit juice's potent inhibition of metabolic function in the intestine [95].

Regarding intestinal

Influence of lipids

High fat meals, as recommended by the FDA in Food-Effect Bioavailability and Fed Bioequivalence Studies [3], result in significantly higher levels of lipids than compared to a fasting state [110], [111]. Persson et al. [112] employed the in vivo single-pass perfusion model in the proximal human jejunum to evaluate the GI response to meal and showed that the tri-, di-, monoglyceride and free fatty acid levels rapidly and markedly increased to 9.5 mM in response to food. Considerable attention

Summary and future prospects

The BCS, as developed by Amidon et al. [8], has proven to be an asset to the FDA by creating a framework by which waivers of in vivo bioequivalence studies for suitable Class 1 compounds can be approved. However, the full predictive utility of a classification system may be realized and facilitated by the BDDCS, as developed by Wu and Benet [10], as this system allows for concurrent consideration of the absorption/transport/elimination interplay thereby extending predictive application to food

Acknowledgements

We greatly appreciate and thank Dr. Selma Sahin for her careful review and helpful editing of this manuscript. This work was supported in part by NIGMS grants GM56847 and GM75900 as well an unrestricted grant from Amgen Inc.

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    1

    Current address: Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.

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