F

AUC]po * doseIV

F is measured by comparing the AUC for oral and i.v. doses from zero to the time point for which elimination is complete.

The calculation of F requires an intravenous reference, that is, a route of administration that guarantees the entire administered drug reaches the systemic circulation. Such studies come at considerable cost, not least because of the necessity to conduct preclinical toxicity tests to ensure adequate safety.

Bioavailability is usually calculated by determining the maximum (peak) plasma drug concentration (Cmax), the time that it takes to reach the peak (Tmax), and AUC. Plasma drug concentration increases according to the extent of absorption; the Tmax is reached, when drug elimination rate equals absorption rate. Bioavailability determinations based on the Cmax however can be erroneous because drug elimination begins as soon as the drug enters the bloodstream.

For drugs excreted primarily unchanged in urine (amphetamine), bioavailability can be estimated by measuring the total amount of drug excreted after a single dose. Ideally, urine is collected over a period of 7-10 elimination half-lives for complete urinary recovery of the absorbed drug.

The Distribution of Drugs in the Body

Once a drug is absorbed into the systemic circulation, distribution occurs throughout the body. The distribution for most drugs in the body is not even; some drugs bind to plasma proteins, while others are sequestered into adipose tissue, and a few have great affinity for bone tissue. Drugs must be highly fat soluble in order to enter the brain. Similarly, fat-soluble drugs can cross the placenta to affect the fetus; these same drugs are also found in the milk of lactating women.

Unevenness of distribution is a barrier to the accurate interpretation of the concentration of a drug in the body and complicates efforts to correlate blood concentrations with behavior. High blood drug concentrations are usually related to greater behavioral effects than low concentrations. However, some drugs (the barbiturates) have passed their peak plasma concentration before peak behavioral effects are seen. In the case of alcohol, some of the above differences do not apply, since alcohol crosses all barriers to distribute uniformly in total body water. Therefore, in the non tolerant individual blood alcohol concentrations are highly correlated with behavioral effects.

In pharmacokinetic terms, the ► Volume of Distribution (VD) also known as the apparent Volume of Distribution is the parameter used as a direct measure of the extent of distribution. VD is purely hypothetical and does not represent an actual physical volume inside the body. It is defined as the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration, by supposing that its concentration is homogeneous, i.e., the average tissue concentration is identical to that ofthe plasma. VD is expressed as:

VD = dose/C0 (initial concentration)

For example, after intravenous injection of 100 mg of a drug whose initial concentration, C0, in plasma is 10 mg/L, the VD would be 10 L. For a given drug, the knowledge of its desirable concentration in blood and VD allows evaluation of the dose to administer.

It is possible for VD to be close to a recognizable volume, such as plasma volume (~0.05 L/kg), extracellular fluid (~0.2 L/kg), or total body water (~0.7 L/kg). This would happen if the drug is uniformly distributed in one of these "compartments," but this is rare. Indeed, when a drug binds preferentially to tissues at the expense of plasma (a drug that is highly lipophilic), the plasma concentration will be extremely low (e.g., methadone, D9-tetrahydrocannabinol). This will result in a large VD> that may be larger than the actual volume of the individual itself (>1 L/kg) e.g., digoxin. A large VD implies wide distribution, or extensive tissue binding, or both.

The VD is thus a mathematical method for describing how well a drug is removed from the plasma and distributed to the tissues. However, VD does not provide any specific information about where the drug is or whether it is concentrated in a particular organ. VD may be increased by renal failure (due to fluid retention) and liver failure (due to altered body fluid and plasma protein binding). Conversely VD may be decreased in dehydration.

The ► distribution phase is so called, because distribution determines the early rapid decline in plasma concentration. However, changes in plasma concentration reflect primarily movement within, rather than loss from the body. In time, equilibrium is reached between the drug present in tissue and that in plasma, and eventually plasma concentration reflects a proportional change in the concentrations of drug in all tissues and hence in the body. At this stage decline in drug concentration is only due to the elimination of drug from the body (elimination phase). Two pharmacokinetic parameters describe the elimination phase, the VD (as described above) and the biological or ► elimination half-life.

The elimination half-life of a drug is the time taken for the plasma concentration as well as the amount of drug in the body to fall by one half and is usually denoted by the abbreviation t1/2. Knowledge of the t1/2 is useful for the determination of the frequency of administration of a drug (the number of intakes per day) and to calculate the desired plasma concentration. Generally, the t1/2 of a particular drug is independent of the dose administered (Table 1).

The Elimination of Drugs from the Body

Elimination occurs by metabolism and excretion. Some drugs are eliminated via the bile and others in the breath, but for most drugs the primary route of excretion occurs via the kidneys.

Metabolism: Drugs are eliminated from the body in both changed and unchanged states: that is, part of the drug eliminated is chemically identical to the drug which was administered, and part has been changed (metabolized). The proportion of a drug dose eliminated in a particular state is determined by the nature of the drug, the dose, the route ofadministration, and the physiological characteristics of the user. The excretion of unchanged psychoactive drugs via the urine or faeces is generally inefficient because of their high fat solubility. As a result, fat-soluble substances are metabolized into water-soluble products that can be readily excreted by the kidneys and/or the intestines (Fig. 5).

Drugs are metabolized by specialized proteins called enzymes, which act as catalysts in the metabolic reaction. Most drug metabolism occurs in the liver, although enzymes in the kidneys, gut, lungs, and blood may also aid in the process. In the liver, there are two types of enzymes: microsomal (insoluble) drug metabolizing enzymes, and cytoplasmic (soluble) metabolizing enzymes (which metabolize alcohol and similar drugs). The conversion of a fat-soluble drug to a substance that has sufficient water solubility for efficient excretion may involve several sequential chemical reactions, each step rendering the molecule slightly more water soluble than before (Feldman et al. 1997). Thus many metabolites are often derived from the same parent drug (for example, there are at least 25 known metabolites from tetrahydro-cannabinol (THC), the main psychoactive ingredient of cannabis).

Pharmacokinetics. Table 1. Plasma elimination half-life for a selection of different compounds.

Substance

Half-life

Notes

► Diazepam (Valium)

20-50 h

Rapid absorption and fast onset of action with peak plasma concentration achieved 0.5-2 h after oral dosing. Active metabolite desmethyldiazepam has a half-life of 30-200 h

► Carbamazepine

18-60 h

Carbamazepine exhibits auto induction: it induces the expression of the hepatic microsomal enzyme system CYP3A4, which metabolizes carbamazepine itself

► Haloperidol

14-36 h

Fifty times more potent than chlorpromazine. Rapidly absorbed and has a high bioavailability

► Fluoxetine

1-6 days

The active metabolite of fluoxetine is lipophilic and migrates slowly from the brain to the blood. The metabolite has a biological half-life of 4-16 days.

► Methadone

24-36 h

Orally effective. Exhibits auto induction: it induces the expression of the hepatic microsomal enzyme system CYP3A4, which metabolizes methadone itself

Water

7-10 days

Drinking large amounts of alcohol will reduce the biological half-life of water in the body.

► Alcohol

No half-life

Percentage of alcohol in your blood goes down by 0.015/h at a constant rate. Metabolism is zero-order kinetics (enzymes are saturated, and the rate of disappearance of ethanol in the body is INDEPENDENT of concentration. Thus, concentration falls off linearly, not exponentially. No half-life

Pharmacokinetics. Fig. 5. Schematic representation of where metabolism occurs during the absorption process. The fraction of the initial dose appearing in the portal vein is the fraction absorbed, and the fraction reaching the blood circulation after the first-pass through the liver defines the bioavailability of the drug administered orally (www.nature.com/.../v2/n3/images/ nrd1032-i2.gif, Image at: www.nature.com/.../v2/n3/box/nrd1032_BX3.html).

As the drug becomes progressively less fat soluble it simultaneously loses the ability to cross the blood-brain barrier and to produce a pharmacological effect. However, some drug metabolites are pharmacologically active, producing the same effects as the parent drug. For example, heroin is metabolized to a number of metabolites, including ► morphine, N-morphine, ► codeine, and 6-monoacetlymorphine, all of which have pharmacological properties characteristic of the original drug.

Other drug metabolites can produce a completely different activity from the parent drug. Certain drug metabolites may be even more toxic than the parent drug: Methanol (methyl alcohol) is an example of a drug metabolized to produce two very toxic metabolites, formaldehyde and formic acid. It is these metabolites which are considered responsible for disruption of the acid-base balance in the body and for damage to the optic nerve, both of which pose serious problems in methanol poisoning.

Both types of liver enzymes, microsomal and cytoplasmic, are inducible - therefore, repeated drug exposure causes the enzymes to increase in number; the result is a faster metabolic rate - that is, a more rapid conversion of the ingested drug into its metabolites. This increased metabolic rate (speeding up of the process) can result in increased intensity and speed of onset of drug effects if the original drug was inactive and the metabolites active. This process can result in decreased intensity and duration of effect, if the original drug was active and the metabolites was inactive. Many enzymes are genetically polymorphic, and their presence and number in the body is under genetic control. Three main phenotypes occur in these cases with individuals categorized as extensive, intermediate, or poor metabolizers accordingly. For instance, this applies to ► MDMA (ecstasy) metabolism and nicotine metabolism as a result of the genetic polymorphism of CYP2D6 and CYP2A6, respectively.

► Zero-order elimination is described when a constant amount of drug is eliminated per unit time, independent of the concentration of the compound. Zero-order reactions are typically found when the enzyme required for elimination to proceed is saturated by the drug. Zero-order kinetics explains when an individual, who drinks 20 units of beer before midnight will fail a breathalyzer test at 8 am the following morning. In this instance, the pathways responsible for alcohol metabolism are rapidly saturated and work to their limit. The removal of alcohol through oxidation by ► alcohol dehydrogenase in the liver is thus limited. Hence the removal of a large concentration of alcohol from blood may follow zero-order kinetics.

Excretion: The kidney acts as a pressure filter through which the blood passes. Most of the water and some of the dissolved substances contained in the blood are reabsorbed during its passage through the kidney. Substances that are fat soluble tend to diffuse back into the bloodstream, whereas residual water and unreabsorbed substances are eliminated during urination. The process of reabsorption and active excretion in the tubules of the kidneys and the time lapse between urine formation and urination, make it is difficult to use urine concentrations of drugs and drug metabolites as a base for accurate estimates of blood concentration of these substances. The drug concentrations determined in urine drug screening are therefore, only a rough indication of blood concentrations (Jenkins 2008). Salivary drug concentrations on the other hand have a much better correlation with blood (Wollff et al. 1999).

The intestines are a site of drug excretion as well as a site of drug absorption. Some drugs and drug metabolites have chemical characteristics which cause them to be actively secreted (or "pushed out'') into bile as they pass through liver cells, and the drug-containing bile then empties into the intestines. Thus, these drugs and metabolites may be excreted in the faeces. As is the case with the kidney, however, the net excretion by this route may be greatly reduced by subsequent reabsorption into the bloodstream of the fat-soluble compounds (including psychoactive drugs) further along in the intestines. In this instance, the drugs will go through the process of excretion all over again (► enterohepatic cycling), and the drug effect may be prolonged.

Volatile drugs such as solvents are commonly excreted in the breath and for general anesthetics; breath may be the major route of elimination. For substances such as alcohol however, it is a minor route. Nevertheless, it is possible through stimulation of breathing to increase the loss of drug from the body. Since the amount excreted in the breath can be reliably related to the blood level, the concentration of alcohol in the breath, as measured by the Breathalyzer test, serves to estimate the degree of intoxication. There are many routes of elimination, including sweat and saliva (and in lactating women, milk) and these all play a role in drug elimination. Though the latter are minor routes, they can be important in forensic analysis.

Just as the parameter, VD is required to relate blood concentration to the total amount of drug in the body, so there is a need to have a parameter to relate drug concentration to the rate of elimination. ► Clearance, denoted by CL, is that factor. The CL of a drug is the volume of plasma from which the drug is completely removed per unit time. The elimination half-life is related to CL and VD by the following equation:

In clinical practice, this means that it takes just over 4.7 times the t1/2 for a drug's concentration in plasma to reach steady state after regular dosing is started, stopped, or the dose changed (Table 2). For example, methadone has a half-life of 24-36 h; this means that a change in the dose will take the best part of a week to have full effect. For this reason, drugs with a very long half-life (e.g., amiodarone, elimination t1/2 of about 58 days) are usually started with a loading dose to achieve their desired clinical effect more quickly (Hallworth and Watson 2008).

Pharmacokinetics. Table 2. The elimination of a compound from the systemic circulation expressed as a function of its half-life.

Number of half-lives

Fraction remaining

Percentage

elapsed

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Anxiety and Depression 101

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