Doseresponse Relationships

The relationship between the dose of a drug administered and the response evoked is a pillar of pharmacology that is central to quantitative analysis of intersub-ject variability in human drug responses. Traditionally, two models have been used in pharmacogenetics to describe the dose-response relationship. One model involves the measurement of the frequency of the response relative to the drug concentrations (or doses) to produce a quantal dose-response relationship. Applications of this model are represented by the frequency distributions in Figure 2.1. The second model involves the measurement of the intensity of a specified response relative to the concentration (or dose) of the drug to produce a graded dose-response relationship as shown in Figure 3.1. This model assumes there is no safe level of exposure and is represented by a linear (or no-threshold) relation between dose and response. A third model, the hormetic dose-response relationship, challenges these traditional models. Hormetic dose-responses are biphasic, displaying either a U-shape, or inverted U-shape, depending on the endpoint measured (Figure 3.2).

Strictly speaking, the concentrations used in any of these models should be those present at receptor sites, but because they are technically so difficult to measure, the concentration of the drug in blood (or plasma or serum), or the drug dosage (amount administered), is usually substituted for them in these relationships, as explained later (see p. 58). Quantal and graded relationships are used to search for different pharmacogenetic phenotypes that may be present within drug responder populations, but they are applied in different ways.

Quantal Dose-Response Relationships

The need for quantal measurements is particularly acute in pharmacogenetics because the effects of Mendelian characters are ''all-or-none'' phenomena. Such responses cannot be graduated because the determinant allele is either present or

Figure 3.1 Theoretical graded dose-response curves for different types of pharma-cogenetic variation. The normal dose-response curve is labeled in each panel. (A) In one type of variation, the maximal response is deficient (1A) or supranormal (1B) at all concentrations of the drug, but the concentration required for half-maximal response is normal. (B) In the other type of variation, the maximal response is normal at elevated (C2B), or decreased (C2A), drug concentrations.

Figure 3.1 Theoretical graded dose-response curves for different types of pharma-cogenetic variation. The normal dose-response curve is labeled in each panel. (A) In one type of variation, the maximal response is deficient (1A) or supranormal (1B) at all concentrations of the drug, but the concentration required for half-maximal response is normal. (B) In the other type of variation, the maximal response is normal at elevated (C2B), or decreased (C2A), drug concentrations.

not. Likewise, for a monogenic drug-induced disorder, the response specified is observed as ''occurring'' or "not occurring,'' or as "present" or "not present.'' The presence of distinct subgroups of drug responders within populations is evidence for a difference that may be a consequence of true genetic differences (metabolic phenotypes, receptor phenotypes, gender differences, etc.) or of f= o a

Figure 3.2 Hormetic dose-response curves. (A) A low-dose stimulatory and highdose inhibitory response. (B) A low-dose inhibitory and high-dose stimulatory response. (A) Endpoints include growth, fecundity, and longevity, and (B) endpoints include carcinogenesis, mutagenesis, and disease incidence. (Source: Drawn from Calabrese.5)

Figure 3.2 Hormetic dose-response curves. (A) A low-dose stimulatory and highdose inhibitory response. (B) A low-dose inhibitory and high-dose stimulatory response. (A) Endpoints include growth, fecundity, and longevity, and (B) endpoints include carcinogenesis, mutagenesis, and disease incidence. (Source: Drawn from Calabrese.5)

environmental effects (ill vs. healthy persons, smokers vs. nonsmokers, particular occupational groups vs. the general population, etc.). Frequency distributions for such populations may be unimodal or multimodal. Multimodal distributions may be more readily interpreted because each mode may correspond to a particular phenotype or genotype, and different modes may represent susceptible and non-susceptible subpopulations that are separable. Several examples of genetically heterogeneous populations in which individuals have been classified according to pharmacological criteria into two or more distinct phenotypes of responders are represented by the frequency distributions shown in Figure 2.1.

Unimodal frequency distributions, in contrast to multimodal distributions, may be difficult to interpret because genetic heterogeneity may be hidden within them. Such a distribution is more likely to occur when the measurement of the variability in response is quantitative rather than qualitative. Quantitative

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