Pharmacokinetics and Toxicokinetics

In this section we will look at the key pharmacological principles that are important to understand when managing patients following toxicological exposure.

An appreciation of these concepts is fundamental to understanding factors such as the timeline of drug effects, the rational for certain interventions (e.g. decontamination, enhanced elimination) and how standard pharmacological parameters of drugs can change in overdose (e.g. saturation, protein binding).

• Pharmacokinetics (PK) - Describes the movement of drugs into, around and out of the body.
• Pharmacodynamics (PD) - Describes the effects that drugs have on the body or specific organs.

The terms toxicokinetics and toxicodynamics are often used as an abbreviation for “pharmacokinetics in overdose” and for “pharmacodynamics in overdose”.

After a drug or chemical is swallowed (the most common route of overdose) it must be dissolved and move across the gastrointestinal membrane (absorption). It is then transported (with a variable proportion attached to blood proteins) in the portal blood stream to the liver where it may undergo a degree of (first-pass) metabolism, before entering the systemic circulation.

Once in the systemic circulation it is distributed throughout the body, where drug concentration may differ in various organs. During and after distribution the drug may produce effects by either binding to specific receptors or by having direct effects on tissues.

Elimination occurs most commonly by hepatic metabolism and renal excretion. There is considerable genetic variation for many of these processes including drug transporters, metabolic enzymes and receptor binding.

Absorption refers to the movement of a substance from the site of administration to the blood.

Bioavailability is expressed as a percentage. It is the amount of drug measured systemically after oral administration compared to the same dose given parenterally (considered 100% bioavailable). Bioavailability is dependent on the extent of absorption and the degree first-pass metabolism (for orally ingested agents).

Influences of absorption

Physical and chemical properties of the agent

Of particular importance is the time to dissolution of the agent. Factors affecting this include:

• Formulation (liquid vs tablet vs controlled-release preparation)
• Tablet load (dissolution of a single table is likely to be substantially different from that of many tablets)
• Solubility in the acidic environment of the stomach vs alkaline environment of the small intestine.
• Lipid solubility of the drug (particularly important when considering crossing of GI tract membranes).

The nature of the absorption process

• Passive absorption: Passive diffusion of a drug from a region of high concentration to a region of low concentration. Therefor the higher the concentration difference over a finite distance, the faster the drug transport rate. This process is not energy dependent.
• Carrier-Mediated absorption: Applies to a minority of drugs (5-10%). Examples include gabapentin, L-dopa, β-lactam antibiotics and angiotensin converting enzyme (ACE) inhibitors. There are two categories, active, which uses energy, and facilitated which does not. May be affected by genetic variation, competition for carrier mechanism, saturation at increased doses, anatomical location of absorption.
• Paracellular diffusion: Passive movement between cellular junctions. Minor route of absorption except for a minority of drugs. Most relevant to agents with low molecular weight with high water solubility.

Gastric emptying and intestinal transit times

• There can be some drug absorption from the stomach, but most drug absorption occurs after entry into the duodenum and small bowel.
• Some drugs can slow gastric emptying by pharmacological means (eg anticholinergics, opioids) and some by physical means (tablets can form large masses (pharmacobezoars) particularly sustained release preparations).

First pass metabolism

This is the extent of metabolism occurring after the drug is absorbed but before the drug reaches the systemic circulation. Many drugs undergo some metabolism (particularly in the gut wall or liver) prior to reaching the systemic circulation.

Notable examples of drugs with high first pass metabolism including buprenorphine, insulin, morphine, diazepam and alcohol.

Once a substance reaches the systemic circulation it is distributed around the body. The pattern of distribution depends on factors such as blood flow to various organs and specific drug properties including protein binding and ability to cross cell membranes. These factors vary enormously between drugs. For example, enoxaparin has a very small volume of distribution (5 L), remains largely within the vascular compartment, and does not readily enter cells. In contrast, drugs such as chloroquine, which are highly effective against intracellular pathogens, have a massive volume of distribution (200-800 L/kg) and can achieve intracellular concentrations up to 200 times higher than those of plasma.

Volume of distribution (Vd) is a theoretical volume that represents the extent to which a drug distributes in body tissues in order to produce the measured plasma concentration, assuming no elimination has occurred.

Vd is not an actual physiological volume, but a constant used to estimate or calculate the expected concentration (C) of a drug following administration of a known dose (D).

$$ Expected\ plasma\ concentration\ (C) = \frac {Amount\ of\ drug\ (D)}{Volume\ of\ distribution\ (V_d)} $$

Vd is drug-specific and relatively consistent across individuals of similar demographics (e.g. age, sex, weight, physiological status). For IV administration, this allows reasonably accurate prediction of initial plasma concentration. For non-IV routes, bioavailability must also be considered.

Protein binding describes the reversible interaction between drug and plasma protein or tissue protein. Drugs exist in equilibrium between protein-bound and unbound (free) states, and only the unbound fraction is pharmacologically active and diffusible. Whilst changes in protein binding are generally not very important in clinical medicine, significant clinical effects from altered protein binding may manifest in toxicology or when protein binding >90%. Drug–drug interactions affecting protein binding are rarely clinically meaningful due to compensatory increases in metabolism and clearance.

Most assays measure total (bound + unbound) drug concentration.

There are a large number of enzymes in the body that metabolise drugs. Although some serve other functions, most evolved a few million years ago, presumably as a means of removing substances that were formed by the body or toxins found in the diet.

In order to excrete drugs and toxins effectively they must be made more water soluble and less lipid soluble. Increased water solubility allows for higher concentrations of the substance to remain in solution in the bile, gut or urine. Lower lipid solubility limits the amount of substance reabsorbed across the gut wall or renal tubule post excretion.

Biotransformation is undertaken by two major enzymatic changes, named phase-I and phase-II reactions.

• Phase-I reactions: These consist of reduction, oxidation or hydrolysis and serve to convert lipophilic drugs into more polar molecules by adding, or exposing, a polar functional group (e.g. -NH2 or -OH). These are often small changes, meaning that the resultant substance (metabolite) may continue to have biological activity.
• Phase-II reactions: These are also known as conjugation reactions and involve attaching a relatively large water-soluble molecule (e.g. glutathione, sulphate) to the drug. This requires the presence of a reactive oxygen group to undergo conjugation, which is not always present, hence the need for phase-I reactions.

The two phases have varying anatomic distribution and capacity. Consequently, some generalisations can be made:

• Conjugative metabolism (phase II) can be described as high capacity, low specificity and anatomically robust. It is therefore hard to saturate and relatively resistant to disease.
• P450 metabolism (Phase-I) is low capacity, highly specific, genetically determined and located in sites that are frequently affected by disease (most notably the liver). It is therefore the site of much of the clinically important altered drug metabolism mediated by disease and drug interactions.

Drugs can be excreted unchanged or as metabolites. The main routes of excretion are via the urine and bile (and then faeces). Other routes of lesser importance are expiration in air, sweet and breast milk.

Excretion in the bile is generally or water-soluble metabolites, whilst both unchanged drugs and metabolites are excreted in the urine.

The rate of renal excretion can be influence by several factors. Entry into the urine may be by passive filtration or active secretion. There may also be passive diffusion back into the blood as water and salts are reabsorbed (a factor largely determined by the lipid solubility of the molecule) or active reabsorption by a specific transport system.

The lipid solubility of a filter substance may in turn be influenced by the pH or the urine. For example, drugs that are acids are more lipid-soluble at low pH and therefore increasing the pH of the urine can potentially decrease the amount of passive resorption.

Clearance (Cl) is the volume of plasma (or blood) from which a drug is completely removed per unit time. It is expressed as volume/time (e.g. mL/min or mL/hr).

It can be estimated by the formula: $$Clearance\ (mL/min) = \frac{Rate\ of\ elimination\ (mg/min)}{Plasma\ concentration\ (mg/mL)}$$

Drugs can be cleared via:

• Kidneys (renal excretion)
• Liver (metabolism, biliary excretion)
• Lungs
• Organ-independent metabolism (plasma esterases, Hofmann elimination)

Total body clearance is the sum of all individual organ clearances: $$Total\ body\ clearance = Cl_{renal} + Cl_{hepatic} + Cl_{lung} + ...$$

For a specific organ, the clearance is a function of blood flow through that organ, and the proportion of drug that is removed during each pass of the organ (extraction ratio). Thus, ↓ renal blood flow (e.g. shock) will ↓ renal clearance. $$Cl_{renal} = Renal\ blood\ flow\ × Renal\ extraction\ ratio$$

First-order kinetics describe a constant fraction of a drug eliminated per unit time. Here, the plasma concentration of a drug declines exponentially. Clearance remains constant because the rate of elimination is proportional to the drug plasma concentration. For most drugs at therapeutic doses, the body's capacity to metabolize or eliminate the drug is not saturated, so elimination follows first-order kinetics.

Half-life (t½) generally refers to the elimination half-life of a substance, and is the time required for a drug concentration to fall to half its original value. It is related to volume of distribution and clearance by the following formula. $$t½ = \frac{0.693\ × V_d}{Cl}$$

Zero-order kinetics describe a constant mass of a drug eliminated per unit time, regardless of its plasma concentration. This occurs because the enzymes responsible for metabolism become saturated and only a fixed amount of drug is eliminated per unit time. The plasma concentration of the drug declines linearly. Classic examples include ethanol and phenytoin.

Further Reading:

1. Evans WE, McLeod HL. Pharmacogenomics Drug disposition, drug targets, and side effects. N Engl J Med 2003;348(6):538-550. PDF
2. Martin J, Fay M. Cytochrome P450 drug interactions: are they clinically relevant? Australian Prescriber 2001;24(1):10-12. PDF
3. Roberts D Buckley N Pharmacokinetic considerations in clinical toxicology: clinical applications. Clin Pharmacokinet. 2007;46(11):897-939. PDF