William E. Schreiber - An Introduction to Testing for Drugs of Abuse

There are four steps in a drug's journey through the body: (i) absorption, (ii) distribution, (iii) metabolism, and (iv) excretion. These processes determine the time frame during which a drug can be detected in blood, urine, and other body fluids. They also determine the rate at which new compounds (i.e., metabolites) appear after a drug is taken. The study of drug absorption, distribution, metabolism, and excretion – what the body does to a drug – is called pharmacokinetics .

Absorption is the process by which drug molecules enter the bloodstream. The rate of this process depends on the route of administration.

Other routes exist (e.g., sublingual, intramuscular or subcutaneous injection), but they are not typically used with illicit or diverted prescription drugs.

Once a drug has entered the circulation, it is transported through the body and diffuses into tissues. This process is influenced by several factors.

Blood flow – drugs are more rapidly distributed to areas of the body with a high rate of blood flow. For most drugs of abuse as well as many prescription medications, the main target organ is the brain, which is well perfused (15% of cardiac output in the resting state).

Chemical structure – drugs that are lipophilic and are not ionized more readily cross lipid bilayers and enter cells.

Protein binding – when bound to plasma proteins (mainly albumin), drugs cannot freely pass through capillary walls and enter tissues. The degree of plasma protein binding therefore affects the amount of drug that reaches its target.

Drugs that are very lipid soluble may distribute into adipose tissue, accumulate there, and eventually diffuse back into the circulation. This can prolong the action of the drug, and it increases the length of time a drug or its metabolite(s) can be detected in blood or urine.

The purpose of metabolism is to transform lipid‐soluble compounds, which readily enter tissues, into a more water‐soluble form that can be excreted. This occurs in two phases.

Phase I – drug molecules are chemically altered by oxidation, reduction, or hydrolysis. These reactions are catalyzed by enzymes in the liver and, to a lesser extent, in other tissues. The most important drug‐metabolizing enzyme system, cytochrome P450 (CYP), contains multiple isoforms that act on a wide variety of drugs. The resulting products are usually inactive or less active than the parent drug. However, in some cases the metabolite has similar or even greater potency.

Phase II – metabolites from phase I, or in some cases the unchanged drug, are conjugated to a water‐soluble group. This usually involves the addition of glucuronic acid or sulfate to an available –OH on the drug molecule ( Figure 2.1). The reactions are catalyzed by UDP glucuronosyltransferase and sulfotransferase enzymes, respectively.

Figure 2.1 Structures of uridine diphosphate (UDP) glucuronic acid and phosphoadenosine phosphosulfate (PAPS), which serve as donors for glucuronic acid and sulfate in phase II reactions. The glucuronic acid and sulfate groups are indicated by rectangles. Addition of either group to a drug molecule increases its water solubility and facilitates excretion in urine and/or bile.

The rate of metabolism varies among individuals. Genetic polymorphisms in CYP and other drug‐metabolizing enzymes affect their activity and can accelerate or slow down the rate of drug transformation. People who are slow metabolizers may experience toxicity from a drug at doses considered therapeutic. Conversely, rapid metabolizers require more drug to reach therapeutic levels in blood.

Drugs and their metabolites are primarily excreted by two routes: (i) glomerular filtration into urine and (ii) transport into bile.

The kidneys remove most drugs and their metabolites from the body. The pH of the glomerular filtrate affects the excretion of weakly acidic and basic drugs, because ionized molecules are not reabsorbed by renal tubules. Molecules that are smaller and more water soluble are usually excreted in this way.

Biliary excretion requires active transport of drugs and metabolites out of liver cells and into the biliary system. Bile flows into the duodenum, and its contents are ultimately discharged in feces. Drugs that are larger (molecular weight [MW] >300) and more lipophilic are preferentially excreted in bile.

Other routes of excretion exist but are less important. Volatile compounds can diffuse out of capillaries in the alveolar wall and enter the air spaces of the lungs, from which they are exhaled (e.g., ethanol). Excretion of drugs in breast milk may affect infants who are breastfeeding.

Disease of the kidneys or liver can impair excretion, causing drug levels in blood and other body fluids to rise.

1 Correia, M.A. (2012). Drug biotransformation. In: Basic and Clinical Pharmacology, 12e (eds. B.G. Katzung, S.B. Masters and A.J. Trevor), 53–68. New York: McGraw‐Hill.

Pharmacology Education Project

www.pharmacologyeducation.org/clinical‐pharmacology/clinical‐pharmacokinetics

Drug Absorption

www.msdmanuals.com/professional/clinical‐pharmacology/pharmacokinetics/drug‐absorption

Drug Bioavailability

www.msdmanuals.com/professional/clinical‐pharmacology/pharmacokinetics/drug‐bioavailability

Drug Distribution to Tissues

www.msdmanuals.com/professional/clinical‐pharmacology/pharmacokinetics/drug‐distribution‐to‐tissues

Drug Metabolism

www.msdmanuals.com/professional/clinical‐pharmacology/pharmacokinetics/drug‐metabolism