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DRUG ABSORPTION

The term lag time refers to the time elapsing between ingestion of an oral medication and its first appearance in the systemic circulation (see Figure 2). For most drugs, it generally falls between 5 and 45 minutes. For ethanol (drinking ALCOHOL, which is also called ethyl alcohol), however, the lag time may be very short, because the drug is already a liquid at the time it is ingested, and a significant component of absorption probably occurs across the gastric mucosa as well as in the proximal small bowel (Frezza et al., 1990). The physicochemical features of the drug contribute importantly to the time necessary for dissolution and therefore to the lag time. All else being equal, drugs in solution have shorter lag times than those administered in suspension form; they are, in addition, more rapidly absorbed than capsule preparations and, finally, tablet preparations. For any given solid dosage form, lag time and absorption rate are likely to be shorter if the drug particles are more finally subdivided. Sustained-release (time-release) drug formulations are deliberately prepared to have long lag times and slow absorption rates, thereby avoiding drug effects associated with the peak concentration.

Absorption rate refers to the time necessary for the drug to reach the systemic circulation once the absorption process actually begins. Pharmacokinetic models can be applied to assign a half-life value to the process of absorption. Values of absorption half-life tend, however, to be of low statistical stability, and it is increasingly common to characterize the absorption process using the observed peak plasma concentration (c_max) and time of peak concentration (t_max). The t_max is actually a composite of the lag time plus the time necessary to reach peak concentration once absorption starts (Figure 2). In general, fast absorption implies a high value of c_max and a short value of t_max; slow absorption implies a long t_max and a low c_max. Again, sustained-release drug preparations are deliberately formulated to produce long lag times and slow absorption, thereby delaying and reducing the c_max after an oral dose. Drug absorption tends to be slower when medications are taken during or just after a meal, rather than in the fasting state (before a meal, on an empty stomach).

For these reasons, the ethanol in alcoholic beverages is relatively rapidly absorbed after oral ingestion. The popular lore that alcohol bas a greater effect when taken on an empty stomach probably has a physiological basis, since peak concentrations will be higher and earlier when alcohol is taken in the fasting state. BENZODIAZEPINE derivatives (tranquilizers) clearly are not primary drugs of abuse and are seldom subject to misuse by the great majority of patients; however, benzodiazepines may be taken for nontherapeutic purposes by some substance abusers (Woods, Katz, & Winger, 1987, 1992; Shader & Greenblatt, 1993). The preference of specific benzodiazepines by drug abusers appears to be closely related to their rate of absorption. That is, rapidly absorbed benzodiazepines, leading to relatively high values of c_max shortly after dosage, appear to be preferred by drug abusers. The benzodiazepine diazepam (Valium), for example, is much more rapidly absorbed than is oxazepam (Serax or Serenid). In controlled laboratory settings, diazepam is more easily recognized as a potentially abusable substance by experienced drug users, and it is also preferred by this group to oxazepam (Griffiths et al., 1984a, 1984b). This preference also appears to be supported by epidemiological studies of PRESCRIPTION DRUG misuse (Bergman & Griffiths, 1986).

Some orally administered medications reach the systemic (blood) circulation in small or even negligible amounts relative to the dose ingested. Incomplete absorption from the gastrointestinal tract sometimes explains this. However, oral medications may be poorly available to the systemic circulation even if they are well absorbed. This is explained by the phenomenon termed presystemic extraction, which results from the unique anatomy and physiology of the gastrointestinal circulation (Greenblatt, 1993). Orally administered medications are absorbed into the portal rather than systemic circulation (Figure 3), and portal blood drains directly into the liver. Many drugs that are avidly metabolized in the liver may therefore undergo substantial biotransformation before reaching systemic blood. Some drugs may also be metabolized by the gastrointestinal (GI) tract mucosa. First-pass hepatic metabolism together with GI tract metabolism is collectively termed presystemic extraction. COCAINE, for example, is not favored as a drug of abuse by the oral route, because of nearly complete presystemic extraction, allowing only small amounts of the intact drug to reach the systemic circulation (Jatlow, 1988; Jeffcoat et al., 1989).

DRUG DISTRIBUTION

The process of distribution is an important determinant of pharmacokinetic properties, as well as the time course of action, of most centrally acting drugs, including those that are subject to abuse. Drugs reversibly distribute not only to their site of action in the brain but also to peripheral sites such as adipose (fat) tissue and muscle, where they are not pharmacologically active (Figure 1). Only a small fraction of the total amount of a psychotropic drug in the body goes to the brain. An even smaller fraction actually binds to the specific molecular recognition site (receptor). The extent of distribution of a psychotropic drug is determined in part by lipid (fat) solubility (how well a substance dissolves in oils and fats; lipophilicity), which is related to molecular structure and charge. Most psychotropic drugs are highly lipid-soluble. Drug distribution is also determined by some characteristics of the organism: the relative amounts of adipose and lean tissue, blood flow to each individual tissue, and the extent of drug that binds to plasma protein. The overall extent of drug distribution throughout the body can be quantified by the pharmacokinetic volume of distribution, which is a ratio—the total amount of drug present in the body divided by the concentration in a reference compartment, usually serum or plasma. Lipid-soluble psychotropic drugs, as well as drugs of abuse, typically have very large pharmacokinetic volumes of distribution, which may exceed body size by ten-fold or more. Although the drug cannot actually distribute to a space larger than the body, low plasma concentrations resulting from extensive uptake into peripheral tissues can yield a large apparent pharmacokinetic volume of distribution (Figure 4).

Drug distribution influences both the onset and the duration of drug action—as well as the observed value of elimination HALF-LIFE. After an intravenous (IV) injection, lipid solubility allows for the rapid crossing of the lipoidal blood-brain barrier, leading to a rapid onset of pharmacological action (drug effect). In behavioral terms, then, drug-taking produces immediate reinforcement. The duration of a drug's action, however, is determined mainly by the extent of its peripheral distribution. Plasma levels of lipid-soluble psychotropic drugs will decline rapidly and extensively after a single intravenous dose, because of peripheral distribution rather than elimination or clearance (Figure 5). A similar principle holds after oral administration of rapidly absorbed drugs (de Wit & Griffiths, 1991). Since duration of action after a single dose is determined more by distribution than by elimination or clearance, it is generally not accurate to equate elimination half-life and duration of action.

CLEARANCE AND ELIMINATION

The terms clearance and elimination half-life are commonly used to describe the bodily process of drug removal or disappearance. These two concepts are related but are not identical. Clearance is the most important, since it is a unique independent variable that best describes the capacity of a given organism to remove a given drug from its system. Clearance has units of volume divided by time—for example, milliliters/minute (ml/min) or liters/hour (L/h)—and is the total amount of blood, serum, or plasma from which a substance is completely removed per unit of time. Clearance is not identical either to the rate of drug removal or to the elimination half-life. For most psychotropic drugs, clearance is accomplished by the liver via processes of bio-transformation that change the administered drug into one or more metabolic products (Figure 6); this is commonly called detoxification by the liver. The metabolites may appear in the urine, but the liver is still the organ that effects clearance. For drugs cleared exclusively by the liver, the numerical value of clearance cannot exceed hepatic blood flow.

Elimination half-life is described in units of time; it can be seen as the time necessary for the plasma concentration to fall by 50 percent after distribution equilibrium has been attained. The elimination phase of drug disappearance—at which time the concept of elimination half-life is applicable—may not be attained until completion of an initial phase of rapid drug disappearance resulting from peripheral distribution (see Figure 5). As discussed earlier, the duration of action of a single dose of a psychotropic drug is not necessarily related to its elimination half-life.

Pharmacokinetic theory yields the following relationship between a drug's elimination half-life, volume of distribution (Vd), and clearance: The independent variables, appearing on the right side of the equation, are Vd, the physicochemically determined property reflecting the extent of distribution, and clearance, having units of volume divided by time, quantifying the capacity for drug removal. Elimination half-life is dependent on both of these. Note that a drug may have long elimination half-life, due either to a large Vd, a low clearance, or both.

PHARMACOKINETICS VERSUS PHARMACODYNAMICS

In contrast to pharmacokinetics, PHARMACODYNAMICS is the quantitative study of the time course of drug action. If drug distribution to the site of action occurs by passive diffusion from the systemic circulation, and if the intensity of drug action depends on the degree of RECEPTOR occupancy both in time and in quantity, then pharmacokinetics and pharmacodynamics are necessarily related. Kinetic-dynamic modeling, discussed in detail elsewhere (Greenblatt & Harmatz, 1993), addresses this relationship mathematically, by directly evaluating concentration versus effect. In the fields of psycho-pharmacology and substance abuse, kinetic-dynamic modeling is a major challenge, since (1) clinical drug effect (pharmacodynamic response) often is difficult to measure reliably and since (2) measured drug concentrations in systemic serum or plasma do not always parallel those at the central site of action. Nonetheless, recent advances in kinetic-dynamic modeling have significantly advanced our understanding of the relationship of the pharmacokinetics of psychotropic drugs to their pharmacodynamic effects.

IMPLICATIONS FOR TESTING OF URINE FOR SUBSTANCES OF ABUSE

Mandatory unannounced testing of urine samples for illegal drugs of abuse is conducted to detect and deter the use of these drugs, as well as to prevent potentially dangerous impairment of performance. The application of the fundamental principles of pharmacokinetics and pharmacodynamics, however, clearly indicates that urine testing is the wrong way to approach these objectives (Greenblatt, 1989; Greenblatt & Shader, 1990).

HEROIN, cocaine, and MARIJUANA, the principal illegal drugs of abuse, are subject to hepatic clearance, so urinary excretion is in the form of drug metabolites rather than the originally taken parent compounds (Agurell et al., 1986; Jatlow, 1988) (see Figure 6). As such, analytical methods for chemical testing of urine samples must be devised to detect these metabolites (Friedman & Greenblatt, 1986) (see Table 1). Screening IMMUNOASSAYS are notoriously insensitive, and many actual drug users will escape detection by the screening test if the urine concentrations are below an arbitrary cutoff (Burnett et al., 1990). Negative tests can also be produced by dilution of urine via water loading (Lafolie et al., 1991) or by a variety of adulterants that interfere with analytical procedures (Schwarzhoff & Cody, 1993; Mikkelson & Ash, 1988). To complicate matters, immunoassays are nonspecific and have an unacceptably high false-positive rate. Most urine-testing programs deal with the false-positive problem by performing confirmatory tests on all positive results from the initial screening (Figure 7). However, even a positive test that is confirmed by gas chromatography/mass-spectroscopy does not conclusively identify that individual as a drug user. Positive urine tests may be produced by passive inhalation or dermal absorption, as (ironically) may occur in law-enforcement officials engaged in drug-enforcement activities (Baselt, Chang, & Yoshikawa, 1990; Elsohly, 1991). Recent evidence suggests that some nondrug-using individuals may excrete heroin metabolites resulting from foodstufts (poppy-seed cake) or from endogenous metabolism (Hayes, Krasselt, & Mueggler, 1987; Mikus et al., 1994). Thus evaluation of the problems of analytical chemistry inherent in urine testing indicates that a negative test cannot rule out illegal drug exposure, nor can a positive test confirm it.

From a pharmacokinetic—pharmacodynamic standpoint, urine is an excretory product and not a body fluid. Urine concentrations of drug metabolites bear little relation to parent-drug concentrations in blood or at the site of action—the concentrations that actually determine pharmacodynamic effect (Osterloh, 1993). Even if chemically accurate, a "positive" urine test for a substance of abuse provides no useful information on the quantity of drug exposure, the duration or chronicity of exposure, or the pharmacodynamic effect of the drug at the time the urine sample was taken, or any time prior to or after that. A positive test does not con-firm intoxication or impairment from that drug at any time, nor does a negative test rule them out. Thus, as a general rule, urine-testing programs are without adequate scientific foundation and cannot possibly attain the stated objectives (Greenblatt, 1989; Greenblatt and Shader, 1990; Sutherland, 1992). This does not mean that carefully controlled tests do not exist—for a discussion of this see DRUGTESTING AND ANALYSIS.

Detection and prevention of performance impairment in the workplace can, however, be achieved by the systematic testing of performance, using validated methods under properly controlled conditions. Such testing procedures would detect potentially dangerous impairment not only from illegal drugs of abuse but also from other causes, including use of legal substances (such as alcohol or antihistamines), sleep deprivation, other medical or psychiatric illness, or episodes of interpersonal stress. Chemical analysis of blood (not urine) could provide chemical confirmation for cases in which drug-induced performance impairment is suspected, provided a research database is available to link blood concentrations to probable impairment, as exists in the case of alcohol (ethanol). Such an approach would provide a fair and direct method of coping with this problem.

COMMENT

A comprehensive approach to understanding the biological bases of substance abuse must combine the neurochemical and molecular mechanisms that underlie the behavioral effects of these drugs, as well as understanding their properties of absorption, distribution, and clearance. Advances were made in the 1980s and will continue to be made as research techniques in both disciplines become increasingly refined.

ACKNOWLEDGMENTS

Research supported by Grants DA-05258 and MH-34223 from the DEPARTMENT OF HEALTH AND HUMAN SERVICES.

The author is grateful for the collaboration of Richard I. Shader, Lawrence G. Miller, Jerold S. Harmatz, and Domenic A. Ciraulo.

(SEE ALSO: Abuse Liability of Drugs: Testing in Humans; Benzodiazepines; Benzodiazepines: Complications; Pharmacokinetics of Alcohol; Psychomotor Effects of Alcohol and Drugs)

DAVID J. GREENBLATT