A human pharmacokinetic study typically results in a mathematical description of drug concentration changes in plasma over time. The value of these data and of their use varies according to patient circumstances. During drug development, this knowledge is essential to develop guidelines for ensuring safe and effective dosage regimens in clinical trials. In clinical practice, plasma concentration measurements are useful to guide dosage adjustments to reach targeted steady-state concentrations of lithium, some anticonvulsant mood stabilizers, and clozapine. In the United States, the low utilization of tricyclic antidepressants and conventional antipsychotics has narrowed the scope of plasma drug concentration monitoring in psychiatry. However, a resurgence of interest is occurring as the search for biomarkers of drug efficacy and tolerability is increasing in drug development (Sunderland et al. 2005). Even without patient-specific drug concentration data, some knowledge of population pharmacokinetic parameters is clinically useful. Population estimates of drug and metabolite half-life can predict the time required for washout from the body once drug dosing is discontinued. This is useful for predicting the overlap of drug in the body when switching among antidepressants or antipsychotics, the presence of drug in the body during anesthesia for surgical procedures, and the probability of a drug-drug interaction when initiating new pharmacotherapy. Such information is useful when prescribing fluoxetine, for example, which produces an active metabolite, norfluoxetine, with an elimination half-life estimated between 4 and 16 days. Thus, an interval as long as 1 month may be necessary after discontinuing fluoxetine before initiating treatment with a monoamine oxidase (MAO) inhibitor to minimize the possibility of developing a serotonin syndrome. The use of slow-release microspheres for injection of risperidone results in an extended drug half-life that predicts continual accumulation to a steady state over four injections given every 2 weeks and sustained drug concentration in plasma for 4-6 weeks after the last injection (Gefvert et al. 2005). The fundamental description of drug disposition begins with studies of single drug doses.

Single-Dose Drug Disposition Absorption

The route of administration is a major determinant of the onset and duration of a drug's pharmacological effects. Intravenous injection ensures that all of the administered drug is available to the circulation. The rate of drug injection or infusion can be used to control completely the rate of drug availability. However, few psychopharmacological drugs are administered intravenously. Intramuscular administration is commonly thought to produce a rapid onset of effect, but exceptions have been documented. For example, drug absorption by this route was slow and erratic with chlordiazepoxide (Greenblatt et al. 1974). The recent availability of intramuscular forms of some atypical antipsychotics will be advantageous for treating psychotic states when rapid tranquilization is desired and oral administration is impractical. For drugs that are equally well absorbed by the intramuscular and oral routes of administration, the total systemic exposure (as reflected in the area under the plasma concentration-time curve

[AUC]) from the two routes should be similar, as should the elimination half-life. A major difference is that the rate of absorption from the intramuscular route may be more rapid. Intramuscular administration of olanzapine 5 mg produced a maximum plasma concentration five times higher than the maximum plasma concentration produced by a 5-mg oral dose with a similar AUC from both routes of administrations (Bergstrom et al. 1999). Most psychoactive drugs are highly lipophilic compounds, which are well absorbed when taken orally. More than 60% of the drugs available on the market are for oral use because of the ease of administration and efficiency of absorption, together with greater patient compliance.

Drug absorption is usually a passive process occurring in the small intestine. The efficiency of oral absorption is influenced by the physiological state of the patient, by formulation factors, and by the timing of administration around meals. Most drugs are best absorbed on an empty stomach. The presence of food or antacids in the stomach usually decreases the rate of drug absorption. Exceptions are sometimes noted. Coadministration of sertraline with food increased peak plasma concentration by approximately 25% and decreased time to peak concentration from 8 hours to 5 hours, with a negligible effect on the AUC (Ronfeld et al. 1997). A partial explanation for this finding is that a food-induced increase in hepatic blood flow could allow more unabsorbed drug to escape first-pass hepatic uptake and metabolism. The significance of this food-drug interaction is doubtful, given that sertraline's therapeutic benefits are reported in association with chronic daily administration. The rate of drug absorption is important when a rapid onset of effect is needed. Normally, the presence of food can be expected to reduce the peak drug concentration achieved in blood or plasma and prolong the time following an oral dose to reach the maximum plasma concentration. The absolute amount of drug absorbed may or may not be affected. Acute drug effects are facilitated by administration apart from meals. Sedative-hypnotic drugs are examples of drugs for which the rate of absorption is clinically meaningful (Greenblatt et al. 1978).

Formulation factors are especially meaningful when a drug effect is associated with achieving a minimal effective concentration (MEC) in plasma. Figure 8-2 shows the predicted plasma concentration-time curves of a drug following a rapid intravenous injection (I), an oral formulation that is completely absorbed with no presystemic elimination (II), an incompletely absorbed oral formulation (III), and an extended-release formulation that results in slow absorption of drug (IV). A formulation with poor bioavailability (III) may not result in a plasma concentration above the MEC, whereas a drug whose absorption is delayed (IV) may retard the onset of effect but maintain an effective concentration for a period similar to the more rapidly available formulations (I, II). The principle of an MEC may apply in antipsychotic therapy, where minimal occupancy of dopamine D2 receptors during a dosage interval may be needed for optimal therapeutic benefit.

FIGURE 8-2. Predicted plasma concentration curves following single doses of a drug by rapid intravenous injection (I), a dosage form with complete bioavailability (II), a dosage form with reduced bioavailability (III), and an extended-release dosage form that reduces the rate but not the completeness of absorption (IV).

Time (Hours)

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved,

MEC = minimal effective concentration.

Recent research in pharmaceutical science has resulted in a variety of systems for controlling the release of oral drugs. These include coated systems, with a core of active drug surrounded by a slow-releasing film; matrix systems, with active drug distributed in erodible gel matrices, and other hydrophilic, swellable, or erodible polymers to slowly dissolve and release drug at predictable rates to produce one or more peak concentrations during a dosage interval. Bupropion, paroxetine, venlafaxine, and the psychostimulants used to treat attention-deficit/hyperactivity disorder (ADHD) are examples of drugs whose clinical utility has been improved by reformulation as sustained- or extended-release dosage forms. Among the immediate-release dosage formulations, a general rank order of products providing the most rapid to the slowest rate of drug release for oral absorption is solutions, suspensions, tablets, enteric- or film-coated tablets, and capsules. Regardless of the dosage formulation selected, the last several hours of declining drug concentration in plasma occur in parallel, because drug elimination rate is unaffected by its rate or extent of absorption (see Figure 8-2). The time at which a terminal elimination phase is clearly observable following a single dose may be delayed, but the terminal elimination half-life is unchanged. Formulation into sustained- or slow-release tablets or capsules may allow drugs with short elimination half-lives, which must be given multiple times per day to maintain an effective concentration, to be effective when administered once or twice daily.

Presystemic Elimination

Many drugs undergo extensive metabolism as they move from the gastrointestinal tract to the systemic circulation (i.e., as they pass through the gastrointestinal membranes and hepatic circulation during absorption). This process is known as the first-pass effect or presystemic elimination and is an important determinant of drug bioavailability after oral administration. Several factors are potentially important in influencing the degree of first-pass effect. A first-pass effect is usually indicated by either a decreased amount of parent drug reaching the systemic circulation or an increased quantity of metabolites after oral administration compared with parenteral dosing. This process is important in the formation of active metabolites for psychoactive drugs and is a major source of pharmacokinetic variability (George et al. 1982).

Presystemic metabolism of drugs is extensively accomplished by cytochrome P450 (CYP) enzymes in the luminal epithelium of the small intestine (Kolars et al. 1992). CYP3A4 represents approximately 70% of total cytochrome P450 in the human intestine. Many useful psychopharmacological drugs are CYP3A4 substrates. Examples of these drugs are listed in Table 8-1 along with substrates, inhibitors, and inducers of other major human CYP isoforms. The liver contains about two- to fivefold greater amounts of CYP3A protein (nmol/mg protein) compared with the intestine (de Waziers et al. 1990). Nevertheless, intestinal CYP3A4 has a profound effect on presystemic drug metabolism. Up to 43% of orally administered midazolam, for example, is metabolized as it passes through the intestinal mucosa (Paine et al. 1996). The exposure of drugs to gut CYP3A4 is not limited by binding to plasma proteins, as can occur with hepatic metabolism. Slower blood flow may also contribute to intestinal metabolism, thereby compensating for the lower quantity of CYP3A4 in the gut compared with the liver.

TABLE 8-1. Substrates, inhibitors, and inducers of the major human liver cytochrome P450 (CYP) enzymes involved in drug metabolism

CYP Substrates enzyme

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