Food effects

The only approved use of methyl parathion is on crops, including crops used as foods. Effective December 31, 1999, the EPA cancelled the use of methyl parathion on many kinds of crops used as foods because of a concern for exposure risks to children and to workers. This action will reduce the risks to families of methyl parathion exposure from food. 

WAGNER D, SPAHN-LANGGUTH H, HANAFY A, KOGGEL A, LANGGUTH P (2001) Intestinal drug efflux formulation and food effects. Adv Drug Deliv Rev. 50 SI3-31. 

B. J. Aungst, N. H. Nguyen, N. J. Taylor, D. S. Bindra. Formulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agent. J. Pharm. Sci. 2002, 91, 1390-1395. 

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

Tab. 21.6. Potential food effects on drug absorption for BCS class I—III drugs.

Adhere Food effects, gastric Inhomogeneity, disease... 

Utilize lymphatic Increase absorption of Food effects persist for... 

In this case, the solubility is extremely poor, even at pH 7, which is considerably above the pKa of troglitazone and corresponds to pH values commonly found in the mid section of the small intestine. Other well-known compounds with analogous behavior are mefenamic acid, glyburide, and phe-nytoin. For troglitazone, the presence of bile salts improves the solubility quite dramatically and lipophilic constituents in the dissolution medium (e.g., in full-fat milk) lead to better dissolution, and in turn better absorption when troglitazone is administered in the fed than the fasted state, as reported by Nicolaides (13). Use of biorelevant dissolution testing permitted these authors not only to qualitatively predict the food effect, but also to predict relative bioavailability of three test formulations. 

In such cases, it is obviously advantageous to use biorelevant dissolution tests to characterize the drug substance, to compare formulations and to make a preliminary assessment of possible food effects. However, for routine quality control work, the manufacture of media containing bile components is not only rather time-consuming but may also present difficulties in terms of quality assurance and validation of the raw materials, as is the case with many chemicals obtained from natural sources. 

For some products, e.g., propanolol extended release formulations (USP 27), a modification of the standard method for enteric-coated dosage forms have been introduced to reflect the change from conditions in the stomach to those in the small intestine. This is a step in the right direction, but to achieve dissolution testing that can differentiate between formulations which are robust and those which are not, and especially to be able to predict food effects on the release from... 

Data have been obtained with this set-up for several different types of MR products and the ability to predict food effects, at least on a qualitative basis, appears to be very promising. An example of a known food effect which can be simulated in vitro is that of a salbutamol MR formulation. The in vitro results are shown in Figure 12. 

Table 8 Biorelevant Media for Studying Food Effects on Release from MR Dosage Forms...

It should be noted that in both guidances BCS-based biowaivers do not apply to food effect BA studies or pharmacokinetic studies other than those designed to test for BE. 

The fed and fasted state may also have significant effects on the absorption or solubility of a compound. Compositions of media that simulate the fed and fasted states can be found in the literature (19) (see also Chapter 5). These media reflect changes in the pH, bile concentrations, and osmolarity after meal intake and therefore have a different composition than that of typical compendial media. They are primarily used to establish in vitro-in vivo correlations during formulation development and to assess potential food effects and are not intended for quality control purposes. For quality control purposes, the substitution of natural surfactants (bile components) with appropriate synthetic surfactants is permitted and encouraged because of the expense of the natural substances and the labor-intensive preparation of the biorelevant media. 

Investigation of potential food effects on drug absorption. 

Investigation of Potential Food Effects on Drug Absorption... 

Consequently, the interplay between solubility and permeability with too many free variables is hindering the researcher or developer from clear statements. Interactions of food with oral absorption may happen at different stages, which again can be titled as dissolution and permeation, and a combined dissolution and permeation assessment might give a deeper insight into possible interaction and food effects. 

Abrahamsson B, Albery T, Eriksson A, Gustafsson I, Sjoberg M (2004) Food effects on tablet disintegration. Eur J Pharm Sci 22 165-172... 

Center for Drug Evaluation and Research, Food and Drug Administration (2000) Guidance for Industry. Food-Effect Bio availability and Fed Bioequivalence Studies. 

Pharmacokinetic concentration-time curves for a drug and ifs mefabolifes are used to identify primary exposure metrics such as AUC, or which are not time-dependent unlike the sequential measurements of concentration over time. A peak plasma concentration of a drug is often associated with a PD response, especially with an adverse event. There can be large inter-individual variability in the time-to-peak concentration, and closely spaced sampling times are often critical to determining the peak plasma concentration accurately in individual patients because of differences in demographics, disease states, and food effects, if any. All these elements are clearly spelled out in the protocols written to conduct these studies. 

Food effect Delays time to peak concentration does not alter extent of absorption 28% decrease in C ax > 1 delay in T ax ( I h) no overall change in AUC... 

Graham, H. (1991) The physical and chemical constitution of foods effects on carbohydrate digestion. In Euller, M.E. (ed.) In vitro Digestion for Pigs and Poultry. CAB International, Wallingford, UK, pp. 35-44. 

Avoidance or attraction of contaminated food Effects on populations and communities... 

The intestinal wall is covered by a mucus layer. This mucus layer prevents direct contact of the lumenal contents with the epithelial membrane. Mucus can be attached onto the lipid membrane by the aid of agar and hydrophilic filter scaffold [64, 65]. This allows the simultaneous assessment of dissolution and permeation. Food effects were adequately predicted using this method. Lofts son et al. used a cellophane membrane as a surrogate for the mucus layer [66]. 

Jones, H.M., Parrott, N., Ohlenbusch, G. and Lave, T. (2006) Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling. Clinical Pharmacokinetics, 45, 1213—1226. 

Like fluconazole, voriconazole (Muijsers et al., 2002) is polar, with moderate aqueous solubility (0.5 mg/mL), resulting in rapid absorption (maximum concentration achieved in less than 2 h) and oral bioavailability (96%). Moderate food effects have been observed. Distribution is wide with a steady-state volume of 4.6L/kg and moderate binding to plasma proteins (58%). 

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