The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in humans

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Abstract

Presystemic metabolism occurring in the intestinal epithelium and/or liver is frequently an important determinant of drug bioavailability after oral administration. Several factors are potentially involved in such a first-pass effect and their modulation may significantly contribute to intra- and interindividual variability in a drug's plasma concentration–time curve. For example, macronutrient intake and nutritional status may alter cytochrome P-450 (CYP) metabolism by the liver, and food per se in the form of a meal can also affect the first-pass metabolism of some drugs. More important changes, however, result from micronutrients and non-nutrients present in food. In the case of charcoal-broiled and smoked foods, polycyclic aromatic hydrocarbons formed during their preparation result in the induction of xenobiotic metabolizing enzymes, especially those regulated by the Ah-receptor, e.g. CYP1A, which are localized in the intestinal tract. A similar effect also occurs following the ingestion of cruciferous vegetables like brussels sprouts and cabbage, which contain indole-related phytochemicals. Such induction can markedly reduce a drug's oral bioavailability. By contrast, the glucosinolate breakdown products of other vegetables produce inhibition of drug metabolism. In the case of phenethyl isothiocyanate-containing watercress, CYP2E1 activity is markedly impaired; however, other organo-sulfur compounds present in, for example, garlic appear to have essentially no effect on drug metabolism. Constituents of grapefruit juice also result in reduced first-pass metabolism, especially for drugs that are CYP3A substrates. Again, this dietary effect is more pronounced in the intestinal epithelium than the liver. A similar, but more generalized, phenomenon also appears to be associated with eating piperine- and capsaicin-containing spices. Possible future applications of such metabolic inhibition include the use of active phytochemicals as bioavailability enhancers for drugs exhibiting a large first-pass effect, and also as cancer chemoprotective agents where CYP-mediated procarcinogen activation is a critical initial step in carcinogenesis. Aging results in a number of physiological changes that potentially can alter drug metabolism and presystemic elimination. By far the most important of these is a reduction in drug metabolizing enzyme activity. Unfortunately, the extent of this effect appears to be unpredictable, both with respect to a specific drug as well as a particular individual. However, the greatest age-related change in oral bioavailability and plasma concentrations is likely to occur with drugs that exhibit a significant first-pass effect (>80%) in young subjects. A similar situation also appears to apply when liver disease is present, especially when this is severe. A further complication in such patients is the presence of vascular shunting, which leads to drug-containing blood by-passing functional enzymes. As a result, plasma levels of drugs that normally exhibit marked first-pass metabolism may be many-fold higher in cirrhotic patients compared to those with normal liver function.

Introduction

The concept that the portal system performs a “gatekeeping” function to protect the systemic organs from potentially toxic xenobiotics following oral ingestion/administration is not new. More than 100 years ago, for example, Lautenbach [1]concluded on the basis of nearly 300 separate studies, that

The experiments which have been given show distinctly that some of the organic poisons are destroyed in passing through the liver, and it is possible that the number of poisons thus destroyed will not prove to be inconsiderable, it being a well-known fact that many of the alkaloids do not have the same effect when given by mouth as when given hypodermically. By the former method the greater portion of the drug passes through the liver on its way to the general circulation, while by the latter all enters directly into the general circulation. It must not, however, be thought that every drug which does not produce its effects when given by the stomach is destroyed by the liver, as it is possible that they are not absorbed from the alimentary canal.

But, beginning in the late 1960s, efforts to quantify the first-pass effect began to be developed. Initially, the focus was on absorption issues related to the formulation aspects of bioavailability [2]; however, a biological component associated with presystemic elimination was subsequently recognized, along with the importance of organ extraction [3]. Because of the major localization of many xenobiotic metabolizing enzymes in the liver, first-pass elimination by this organ was of primary concern. As a result, a fairly comprehensive understanding of the quantitative aspects of this phenomenon and the physiological determinants involved was established, which provided a unifying and predictive approach that still remains valid and useful 4, 5, 6. To a large extent, the potential importance of gastro-intestinal metabolism in the first-pass effect was acknowledged during those years [7]and approaches to quantify its extent in animals were developed 8, 9. However, the possibility of the same phenomenon occurring in humans was generally dismissed because of its perceived minor role and/or the difficulty of its in vivo quantification, separate from any hepatic contribution [10]. The recent recognition that the extent of metabolism by certain enzymes, e.g., CYP3A, in the human gastro-intestinal epithelium may be comparable, or even exceed that by the liver (see Chapter 1) has, however, resulted in increased interest in the role and importance of this site of presystemic elimination. Moreover, a keener appreciation of the different determinants of individual xenobiotic metabolizing enzymes, especially the various cytochrome (CYP) P450 isoforms, is beginning to provide valuable information about factors that may modulate first-pass metabolism in both organs. In this chapter, three such factors are considered with respect to their role, importance and clinical significance in humans; namely, diet, aging and the presence of disease-states. The role of the gastro-intestinal flora in xenobiotic metabolism is not considered, since several articles concerning this area are already available 11, 12.

A first-pass effect following oral administration is generally assessed in vivo by the drug's measured oral bioavailability (Foral), i.e., the fraction of an orally administered dose that reaches the systemic blood sampling site compared to that given intravascularly, usually intravenously. If only the plasma drug concentration–time profile is determined, i.e., no intravenous reference data is available, then bioavailability is relative rather than absolute. Three factors are potentially involved: the fraction of the administered dose absorbed into and through the gastro-intestinal membrane(s) (Fabs), the fraction of the absorbed dose that passes through the gastro-intestinal tract into the hepatic portal blood unmetabolized (FG), and the hepatic first-pass availability (FH). Pulmonary metabolism should also be a factor when the reference dose is administered intravenously; however, this is often neglected on the, generally untested, assumption that for most exogenous agents it is negligible. Therefore, oral availability is defined by the continuous product of the bioavailabilities of the involved first-pass processes [13].Foral=Fabs·FG·FHSince organ bioavailability (F) is determined by its extraction ratio (E), according to the relationship F=1−E, the factors that control the extent of any first-pass effect other than absorption are those contributing to the efficiency of extraction by the gastro-intestinal tract and liver.

Regardless of the particular model chosen to describe the elimination characteristics of the liver [14], the hepatic extraction ratio is determined by the activity of its xenobiotic metabolizing enzyme(s), which may be quantified by the intrinsic clearance of unbound drug (Clintu); the unbound fraction of drug in the blood (fuB); and liver blood flow (QH). By far the most important of these factors with respect to both intra-individual and interindividual variability in first-pass extraction is Clintu. Since fuB often remains constant over the drug's concentration range in vivo, total intrinsic clearance (Clinttotal=Clintu·fuB) is usually the operative determinant. Moreover, after oral drug administration, the area under the drug's plasma concentration–time curve (AUC) is an inverse reflection of this parameter [14]. Thus, differences in hepatic extraction within and between individuals are primarily a reflection of modulation and differences, respectively, in the catalytic activity of the liver's xenobiotic metabolizing enzyme system(s). In many instances, absolute oral bioavailability is not estimated since this requires intravenous administration of the drug. Instead, a relative change in bioavailability is determined, based on the ratio of the AUC values obtained following oral drug administration in each study. It is difficult under such circumstances to determine the relative contributions of altered absorption resulting from a change in the drug's first-pass effect from a difference in systemic clearance. For example, with a drug having a low hepatic extraction rate, a change in intrinsic clearance results in a comparable change in AUC, but this primarily reflects alteration of the elimination half-life, and bioavailability and peak plasma concentrations are hardly affected. By contrast, any change in AUC for a high clearance drug is primarily reflected in the absorption phase, i.e., altered bioavailability and peak levels, rather than the post-absorptive rate of elimination.

In principle, the analogous determinants should contribute to extraction by the gastro-intestinal tract, however, their quantitative inter-relationship is not as well understood as that for the liver. Several factors contribute to this situation because of the unique physiology of the gastro-intestinal tract and the vectorial fashion in which xenobiotics are presented to it. First, the gastro-intestinal tract is not uniform either in its structure or function, and substantial differences are present throughout its length. In particular, its metabolizing ability varies from anatomic region to region and, also, according to the particular enzyme of interest (see Chapter 1). In general, higher catalytic levels are found in the small intestine (duodenum, jejunum), but activity is often present throughout the tract, including the ileum and colon. Since drug absorption following oral administration is frequently most extensive in the small intestine, it is likely that, for many drugs, this location corresponds to the primary site of any gastro-intestinal, first-pass metabolism. On the other hand, metabolism at more distal sites may also be important, as in the case of dietary/environmental procarcinogen activation in the lower bowel, which may be involved in the development of colon cancer 10, 11, 12. Second, xenobiotic metabolizing activity resides primarily in the mucosal epithelial cells and, generally, is greatest in the villous tip and decreases progressively towards the crypt, i.e., metabolizing ability is a differentiated function of the epithelium [10]. Such heterogenous distribution characteristics have recently been confirmed with respect to CYP3A 15, 16, 17, which is involved in the metabolism of many common drugs and other xenobiotics [18]. Because of this differential distribution of enzymatic activity, the development of appropriate quantitative (pharmacokinetic) models is much more difficult for the gastro-intestinal tract than in the case of a more uniform organ like the liver. A further complicating factor is the vascular distribution and supply of systemic blood to the catalytically active enterocytes. Only about 40% of total gastro-intestinal blood flow is distributed to the small intestine and, of this, the epithelial cells only receive about 70% [10]. Furthermore, the mucosal blood supply can vary considerably, depending on the body's physiological state, including the eating and digestion of food. Accordingly, the relationship of blood flow and extraction in the gastro-intestinal tract is more complicated than in other eliminating organs, such as the liver. Another consideration is that drug metabolism following oral administration and absorption occurs during vectorial transport of drug through the enterocyte and prior to it reaching the vasculature. Thus, a true first-pass effect occurs, which is not reflective of any post-absorptive metabolism that may occur through drug transfer from the systemic circulation to the epithelial cells. Also, such initial metabolism within the enterocyte is likely to be limited by intracellular binding rather than that in the systemic circulation. Regardless of these complications, the primary quantitative determinant of gastro-intestinal metabolism undoubtedly reflects the organ's metabolizing capacity at the appropriate location(s) along its length.

Since organ bioavailability equals 1−E, the first-pass effect is a graded phenomenon that increases in extent according to the magnitude of the organ's extraction ratio (E). In practice, however, the term is generally used to indicate the presence of a substantial effect, i.e., E≥0.7. It also follows that intra- and interindividual variability in metabolism/extraction will be more significant for drugs with high extraction ratios, and that the extent of change/difference will be greater with respect to bioavailability than the extraction ratio, i.e., a 10% reduction in extraction from 0.9 to 0.8 caused, for example, by inhibition of metabolism, will result in a 100% increase in bioavailability (10 to 20%).

It must also be recognized that expression of a particular metabolizing enzyme in the gastro-intestinal epithelium and the liver may be independently and non-coordinately regulated. Such tissue-specific regulation is, of course, well-established in the general sense, but there is increasing evidence of its relevance to first-pass metabolism, at least with CYP3A. For example, no correlation was found between CYP3A's catalytic activity determined in biopsied human intestinal samples and hepatic metabolism measured in the same individuals [19]. More recently, data on the separate CYP3A-mediated extraction of midazolam by the intestinal tract and the liver further supports non-linkage of the enzyme's catalytic activity at these two sites [20]. In this study, some individuals with high hepatic extraction ratios had low intestinal extraction values, and vice-versa. In both of these studies, considerable interindividual variability was noted in the extent of CYP3A-mediated metabolism in both organs; however, the range of activity was greater in the intestinal tract because, in some individuals, activity was essentially absent or considerably lower than in others. As a result of such heterogeneity, it is likely that the relative contribution of the intestinal tract and the liver to any overall first-pass effect is not only dependent on the particular drug but also varies between individuals according to the respective levels of metabolic activity. In addition, modulation of such activity may be more localized to one organ than the other. For example, oral administration of an inhibitor or inducer of metabolism may have a greater effect on enzymes in the intestinal epithelium than those more distally located in the liver. Furthermore, the extent of modulation may be related to the level of catalytic activity originally present in the organ; a smaller effect being observed when the amount of enzyme is low compared to that found when there is a higher level of enzyme. In turn, this would be expected to result in differences in responsiveness between individuals with respect to the effects of an inhibitor/inducer. This could account for the observation, for example, that pretreatment with oral erythromycin affects terfenadine's oral disposition to a greater extent in some individuals than others [21]. That is, the interaction may primarily result from inhibition of CYP3A in the intestinal tract rather than the liver and this effect is less pronounced in those individuals with no or low levels of the enzyme. Finally, it is highly likely that the extent of any reduction in first-pass extraction following oral administration/ingestion of an inhibitor will be highly dependent upon the time of administration of that compound relative to the other drug and also the rates of absorption of the two compounds, i.e., the change in intestinal metabolism may be quite transitory.

Section snippets

Effect of diet on drug metabolism and the first-pass effect

The human diet is a complex mixture of macro- and micro-nutrients, as well as naturally occurring non-nutrients and food additives. Moreover, the amount of food ingested and its composition varies according to availability, preference and method of preparation, dietary manipulation, and seasonal and religious factors. A plethora of studies in animals indicate that such differences may affect the metabolism of drugs and other xenobiotics 22, 23. Moreover, epidemiological studies related to diet

General considerations

The topic of age-associated alterations in drug effects has been and continues to be of considerable interest given the changing demographics of most developed countries and the fact that the elderly take a disproportionately high number of medications. In addition, multiple drug therapy, altered physiological/pharmacological responsiveness and, frequently, the presence of several concurrent disease-states makes drug treatment of the elderly particularly challenging. As a result, a large number

Diseases of the gastrointestinal tract

Along with genetic and environmental factors, the presence of disease-states is a major determinant of interindividual and, generally, to a more limited extent, of intra-individual variability in drug disposition and clinical responsiveness. Accordingly, a plethora of investigations have considered pharmacokinetic and pharmacodynamic alterations associated with specific disease processes. A limited number of these have addressed the effects of certain gastro-intestinal diseases on drug

Perspective

Large interindividual variability in oral bioavailability complicates optimal drug therapy and may limit the development of a drug with a small therapeutic index. Accordingly, elucidation of factors contributing to such variance is important and has been the focus of innumerable studies. Generally, the methodological approach has been to define the magnitude of any differences and possible underlying mechanism(s) and, then, to identify possible phenotypic traits that might be quantitatively

Acknowledgements

Supported in part by USPHS grant GM-31304.

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