Estimating Effective Doses

There are three available data types on which to base estimates for an effective dose: human anticancer data; animal antitumor data; and a combination of pharma-cokinetic and in-vitro data. Each type has advantages and disadvantages, but all can provide helpful information. In Part III, we estimate a target dose by using as many of these types as available data allow, then we compare the doses estimated with each to corroborate their values. For most compounds, human data are not available and doses can be estimated using only the last two data types.

If the dose estimate made from each available data type is in general agreement with the others (considered here as within a factor of two), we assume the target dose is relatively well known. In these cases, our target dose is generally chosen as an average of the available estimates. In actuality, a range of target doses may be more fitting, but for simplicity of calculations, we generally choose only one value. Note that the dose estimates we make are for the most part crude approximations based on numerous assumptions. They are useful as a starting point to conceptualize target doses but are still only an initial attempt based on limited data. They provide only ballpark approximations, and much more study is needed.

Use of the third data type, a combination of pharma-cokinetic and in-vitro data, requires additional explanation. Briefly, we assume that a concentration effective in vitro will also be effective when produced in the plasma in vivo. This is not necessarily the case, as is discussed in Appendix B, but this assumption will work for our approximations. After identifying the effective plasma concentration from in-vitro data, we use phar-macokinetic data to determine how large a dose is needed to produce that concentration. (Pharmacokinetic data tell us how a given dose affects the plasma concentration.) The crucial pharmacokinetic parameter in these calculations is called the oral clearance. Simply put, the oral clearance value represents the amount of drug removed from the body per unit of time after oral administration.

Details of the method used to estimate a required dose based on pharmacokinetic and in-vitro data are provided in Appendix J, but a few points are highlighted here. First, oral clearance values can come from three sources: human studies, animal studies, and mathematical models. Values obtained from human studies are the most accurate, but again, few human studies are available. Values from animal data are next in accuracy and to be useful must be scaled to their human equivalent (see Appendix B). For some compounds, even animal values are unavailable. For this reason and as a way to corroborate animal and human values where they exist, the oral clearance can be predicted based on the chemical structure of the compound. I have developed a model to make these predictions; its details and limitations are presented in Appendix I.

The second point about this method is that the effective in-vitro concentration must be known. Although in-vitro data are available for most compounds, the effective concentrations generally vary over a wide range in different studies. Thus it is difficult to choose the most appropriate target concentration. Most of the compounds discussed in this book are effective within the same general range (1 to 50 pM, commonly 5 to 30 mM). To simplify the task of estimating doses, I chose a target concentration of 15 pM for most compounds, a value roughly the average for all the in-vitro studies.

For the phenolic compounds discussed in Chapters 19 and 20, the 15-pM target concentration is modified because these compounds tend to occur in the plasma in the form of conjugates, which are generally less potent than the free, unchanged compound. Conjugates are produced during phase II metabolism (a form of detoxification). Conjugation takes place in the liver as well as in other tissues like the intestinal lining. It is the body's attempt to make a foreign compound more water-soluble and thus more easily excreted in the urine. The conjugates produced during detoxification are comprised of the parent molecule or its metabolites linked to a second, more water-soluble molecule. This second molecule is either glucuronic acid (which is related to glucose), glu-tathione, or sulfate. For the phenolic compounds discussed, glucuronide conjugates predominate in the plasma. We assume here that these conjugates are essentially half as potent as the free parent compound (see Appendix J). Since most phenolic compounds appear in the plasma primarily in their conjugate form, we assume the target concentration of most phenolic compounds is

30 mM, or twice as high as the target of 15 mM used for most other compounds.

A final point is that the magnitude of the dose can affect both the absorption (since absorption is apt to be limited at high doses) and the type and concentration of active metabolites. Thus in addition to limits from safety issues, a human dose can also be limited by its ability to be absorbed or beneficially metabolized. Dose-dependent issues are likely to occur mostly for the phenolic compounds, which generally require the largest doses. In this book we conservatively assume that doses in excess of 1.8 grams per day (600 milligrams three times per day) of any single compound will produce limited gains in plasma concentration and/or will produce a different and less effective mix of metabolites in the plasma. We refer to this 1.8-gram limit as the general linear bioavailability limit (the reasoning behind this is presented in Appendix J). Some exceptions are noted in the text. To illustrate how this limit is used, imagine that the target dose of a compound is 18 grams and the safe dose is 20 grams. For this compound, the maximum recommended dose would be 1.8 grams; it would then need a 10-fold increase in potency due to synergism to make it as effective as an 18-gram dose.

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Detox Diet Basics

Detox Diet Basics

Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful  matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.

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