Pharmacokinetics and Toxicokinetics

Pharmacokinetics and toxicokinetics are key pharmacological principles essential for managing patients after toxicological exposure. These concepts are fundamental for understanding the timeline of drug effects, the rational behind certain interventions (e.g. decontamination, enhanced elimination), and how standard pharmacological parameters of drugs (e.g. saturation, protein binding) can change in overdose.

• Pharmacokinetics (PK): The movement of drugs into, through, and out of the body.
• Pharmacodynamics (PD): The effects drugs have on the body or specific organs.

In toxicology, toxicokinetics and toxicodynamics refer to PK and PD in overdose situations.

After ingestion (the most common route of overdose), a drug must be dissolved and absorbed across the gastrointestinal membrane. It then enters the portal circulation, where it may undergo first-pass metabolism in the liver before reaching the systemic circulation. Once in the systemic circulation, the drug is distributed throughout the body at varying concentrations across different organs (depending on physicochemical factors including protein binding and lipophilicity). Effects occur through receptor binding or direct tissue interaction. Elimination then primarily occurs via hepatic metabolism and renal excretion. Genetic variation can influence drug transport, metabolism, and receptor intereactions, affecting both PK and PD.

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

Bioavailability is the fraction of a drug that reaches the systemic circulation compared to same dose given intravenously (which is considered 100% bioavailable).

Determinants of bioavailability include the following.

Physicochemical properties

• Formulation: liquid vs tablet vs controlled-release preparations.
• Drug concentration: higher dose ingested results in ↑ absorption.
• Solubility in acidic gastric environment vs alkaline environment of the small intestine.
• Lipid solubility.
• Molecule size: smaller molecules are absorbed more easily.

Absorption

• Mechanism of absorption: passive transcellular diffusion (e.g. propranolol), carrier-mediated transport (e.g. L-dopa), paracellular diffusion (e.g. atenolol).
• Route: IV, IM, sublingual, oral, transdermal routes have different rates of absorption.
• Blood flow: ↑ local blood flow results in ↑ absorption.
• Gastrointestinal factors:
  • GI motility: Most drugs are absorbed in the small intestine. ↓ transit time results in ↑ exposure time of drug in a particular GI compartment. Some drugs slow GI motility by pharmacological means (e.g. anticholinergics, opioids) or by physical means (e.g. slow-release tablets which can form pharmacobezoars).
  • Enterohepatic recirculation: Some drugs are excreted by bile and reabsorbed in the small intestine (e.g. valproate).

First-pass metabolism

• Intestinal metabolism.
  • Mucosal enzymes e.g. CYP3A4 metabolizes midazolam into active and inactive metabolites, altering its bioavailability.
  • Gut bacteria may metabolize drugs into active or inactive metabolites.
• Hepatic metabolism.
  • Drugs which undergo high first-pass metabolism include buprenorphine, morphine, diazepam, and ethanol.

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 is 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 routine clinical practice, they can have important consequences in toxicology or when a drug is highly protein-bound (>90%). In these situations, even small changes in protein binding can lead to disproportionate changes in free drug concentration resulting in adverse effects or toxicity. Drug-drug interactions affecting protein binding are rarely clinically meaningful due to compensatory increases in metabolism and clearance.

It is important to note that most laboratory assays measure total (bound + unbound) drug concentration, and not necessarily specifically the free fraction. Therefore, interpreting serum drug levels, particularly for highly protein-bound drugs, requires an understanding of protein binding dynamics and clinical context.

A large number of enzymes in the body are involved in drug metabolism. Although some of these enzymes primarily serve other physiological functions, most are believed to have initially evolved to facilitate the elimination of endogenous substances and dietary toxins. For efficient excretion, drugs and toxins must be made more water-soluble and less lipid-soluble. Increased water solubility allow higher concentrations of the substance to remain in solution within the bile, gut, or urine. Reduced lipid solubility limits the amount reabsorbed across the gut wall or renal tubule after excretion.

Biotransformation occurs through two major types of enzymatic reactions, known as phase I and phase II reactions.

Phase I reactions (aka functionalization reactions) introduce or expose a polar functional group (e.g. –NH₂, –OH), increasing the molecule's polarity. These reactions are predominantly mediated by the cytochrome P450 enzyme family and include reduction, oxidation, or hydrolysis. These chemical modifications are often minor, and the resulting metabolites may also retain biological activity. Phase I metabolism typically results in only a small increase in water solubility. If they are sufficiently polar, phase I metabolites may be readily excreted. However, many require further transformation through a subsequent (phase II) reaction to enhance water solubility and facilitate excretion.

Phase II reactions (aka conjugation reactions) involve the attachment of a highly polar substrate, significantly increasing their water solubility and excretability. Conjugation often requires the presence of a reactive functional group, which may be introduced during phase I metabolism. Examples include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with other amino acids.

These two phases exhibit distinct functional patterns. In general:

• Phase I metabolism exhibits low enzymatic capacity, high substrate specificity, and significant inter-individual genetic variability.
• Phase II metabolism exhibits high enzymatic capacity, low substrate specificity, and is less sensitive to genetic variation and disease. An exception to this is sulfation, which is dependent on the limited availability of the sulfate donor PAPS, and thus has a lower enzymatic capacity ^[1].

Drugs are excreted either unchanged or as metabolites. The primary routes of excretion are via urine and bile (and subsequently feces), with minor routes including exhalation, sweat, and breast milk.

Biliary excretion mainly involves water-soluble metabolites, while urine excretes both unchanged drug and metabolites.

Renal excretion is influenced by several factors. Drugs enter the urine through passive filtration and/or active secretion, and may undergo passive reabsorption (dependent on lipid solubility) or active reabsorption via co-transporters. Lipid solubility of renally excreted drugs is affected by urinary pH. For example, acidic drugs are more lipid-soluble in acidic urine, so alkalinizing the urine can reduce its passive reabsorption and enhance elimination.

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. in 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.