Variability In The Doseeffect Relationship

A major challenge of treating mental illness with drugs is that both pharmacokinetic and pharmacodynamic variability complicate the dose-effect relationship. The presence of active metabolites, the influence of pharmacogenetics, and the effects of combining two or more drugs contribute to variability. Noncompliance with the prescribed treatment plan on the part of the patient can seriously undermine reliability in the expected effects from pharmacotherapy. Physiological differences between patients are another source of variability. The effects of age, weight, and hepatic and other disease states are major factors in pharmacokinetics and pharmacodynamics that indicate the need for individualization of therapy.

Active Metabolites

With the exceptions of lithium and gabapentin, which are renally excreted, drugs used in clinical psychopharmacology are cleared partially or completely by metabolism, primarily in the liver. Many psychoactive drugs produce pharmacologically active metabolites that distribute to the effect sites (see Figure 8-1) to produce pharmacological effects. Like their precursors, metabolites may have multiple pharmacological effects that may be similar to or different from those of the parent drug. Sertraline's metabolite, desmethylsertraline, has about 10% of the activity of sertraline in inhibiting the serotonin (5-HT) transporter, but the metabolite is equipotent with sertraline in its affinity for the hepatic isoenzyme CYP2D6 (Fuller et al. 1995). The major metabolite of risperidone, 9-hydroxyrisperidone, has pharmacological effects similar to its precursor as a dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonist but differs in its affinity for and inhibition of the drug transporter P-gp (Zhu et al. 2007).

When switching therapy from one drug or drug class to another, the presence of any active metabolites should be considered (Garattini 1985). Norfluoxetine, for example, has an average half-life of 8-9 days, much longer than the average of 2-3 days for fluoxetine, its parent drug (DeVane 1994), and is an equipotent serotonin reuptake inhibitor. It may take several weeks for this metabolite to clear the body after discontinuation of fluoxetine (Pato et al. 1991). A similar situation applies to aripiprazole and its active metabolite, dehydro-aripiprazole, which have elimination half-lives of 75 hours and 94 hours, respectively.

Metabolites will accumulate to a steady state in the body in relation to their elimination half-lives and not those of their parent drugs. For a drug that is nearly completely metabolized in the liver, a characteristic of numerous psychoactive drugs, the produced metabolites will always have an elimination half-life that is equal to or longer than the half-life of the parent drug. This is a logical conclusion of considering that a metabolite cannot be eliminated faster than it is formed. Of course, administration of the metabolite as a separate molecular entity apart from the parent drug would produce a drug concentration-time curve independent of any influence of the metabolite being formed from a precursor in vivo. For some drugs, the full expression of direct pharmacological effects may not be expected until both the drug and any important active metabolites have all attained their steady-state concentration. For drugs producing indirect effects when the response depends on second messengers or a cascade of receptor actions, the waiting period for fully expressed effects may be even longer.


Stereochemistry or chirality of drug molecules is an increasingly important consideration in pharmacokinetics. Many psychoactive drugs exist as two or more stereoisomers or enantiomers with distinctly different biological properties and are marketed as the racemic (i.e., 50:50) mixtures of both isomers. Although enantiomers have identical physicochemical properties, they are often recognized as distinct entities by biological systems and may bind to transport proteins, drug-metabolizing enzymes, and pharmacological effect sites with different affinities. As a result, one enantiomer may possess a significant pharmacological effect, while the other stereoisomer may lack similar effects or produce different effects. Enantiomers may also differ in their absorption, metabolism, protein binding, and excretion, leading to substantial differences in pharmacokinetic properties (DeVane and Boulton 2002). Furthermore, one isomer may modify the effects of the other.

The development of single-isomer drugs may offer advantages over use of the racemic mixture. Potential advantages include a less complex and more selective pharmacological profile, a potential for an improved therapeutic index, a more simplified pharmacokinetic profile, a reduced potential for complex drug interactions, and a more definable relationship between plasma drug concentration and effect. Examples of racemic mixtures in current use include methadone, methylphenidate, bupropion, venlafaxine, fluoxetine, and citalopram. Clearly, each drug needs to be considered individually with regard to its development as a single stereoisomer formulation. Recent examples of successful switches to single isomers are escitalopram and dexmethylphenidate.


Inheritance accounts for a large part of the variations observed in the ability to eliminate drugs (see Figure 8-1) among individuals. This forms the basis of pharmacogenetics, which is defined as the study of the genetic contribution to the variability in drug response (Kalow et al. 1986; Price Evans 1993). This term was originally applied to the effect on pharmacokinetics, while pharmacogenomics dealt specifically with genes mediating drug response. More recently, the terms have been used interchangeably. Numerous association studies have been performed of genetic polymorphisms of molecular targets as predictors of disease susceptibility, specific drug response, and tolerability. This topic is covered in the chapter addressing pharmacogenomics (see Chapter 3, "Genetics and Genomics"). The genetic differences in pharmacokinetics that have been detected apply mostly to drug metabolism. The renal clearance of drugs appears to be similar in age- and weight-matched healthy subjects with no defined genetic polymorphisms. Genetic polymorphisms have been identified and defined for some drug transporters, primarily P-gp, and several hepatic enzymes important for the cellular transport and metabolism of many drugs used in psychopharmacology. These genetic polymorphisms are summarized in Table 8-2.

TABLE 8-2. Some genetically determined variations influencing drug pharmacokinetics

Protein (major polymorphisms)

P-glycoprotein (T1236C, G2677T, C3435T)

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