Pharmacokinetics

1. Introduction to Pharmacokinetics
   • The ADME Framework
   • Why Pharmacokinetics Matters in Practice
2. Absorption
   • Routes of Administration
   • Bioavailability
   • First-Pass Metabolism
3. Distribution
   • Volume of Distribution
   • Plasma Protein Binding
4. Metabolism
   • Phase I Reactions
   • Phase II Reactions
   • The Cytochrome P450 System
   • Enzyme Induction and Inhibition
5. Excretion
   • Renal Excretion
   • Other Routes of Excretion
6. Clearance, Half-Life and Steady State
   • Clearance
   • Half-Life
   • First-Order and Zero-Order Kinetics
   • Steady State and Loading Doses
7. The Therapeutic Window
8. Summary
9. Quiz

• Pharmacokinetics is the study of what the body does to a drug, summarised by the four processes of Absorption, Distribution, Metabolism and Excretion (ADME).
• Bioavailability describes the fraction of an administered dose that reaches the systemic circulation. An intravenous dose is 100% bioavailable by definition. The bioavailability of an oral dose is reduced by incomplete absorption and by first-pass metabolism (breakdown of the drug by the gut wall and liver before it reaches the general circulation).
• Volume of distribution (V_d) and clearance (Cl) are the two fundamental pharmacokinetic parameters; together they determine a drug's half-life (t_½, the time for the plasma concentration to halve) and therefore its dosing schedule.
• Most drugs at therapeutic doses follow first-order kinetics, meaning a constant fraction is eliminated per unit time. A steady state (the point where the amount of drug going in equals the amount going out) is then reached after roughly five half-lives. A small but important group, including ethanol, phenytoin and aspirin in overdose, follow zero-order kinetics. Here elimination is saturated, so small dose increases can cause disproportionately large rises in plasma concentration.

Introduction to Pharmacokinetics

Pharmacokinetics, often shortened to PK, is the study of how the body handles a drug from the moment it is administered to the moment the last molecule is removed. Here is a clean way to remember the difference between pharmacokinetics and pharmacodynamics. Pharmacokinetics is what the body does to the drug. Pharmacodynamics is what the drug does to the body.

For a medicine to work, it has to reach its site of action at a sufficient concentration. It must stay there long enough to exert its effect, without ever rising into the toxic range. Pharmacokinetics is considered critical to designing the dosing plan: how much to give, how often, and how to adjust it. A company applying for a UK licence must describe the medicine's pharmacokinetic properties.

The ADME Framework

Almost every question in pharmacokinetics can be filed under one of four headings:

• Absorption: getting the drug into the systemic circulation.
• Distribution: moving it from the blood into the tissues where it acts (and into compartments where it does not).
• Metabolism: chemically modifying it, usually in the liver (mainly by cytochrome P450, or CYP450, enzymes), to make it easier to excrete.
• Excretion: removing it from the body, predominantly via the kidneys.

Sorting a problem under one of these headings tells you where to look. A drug that is not working may be poorly absorbed. A drug that builds up to toxic levels may be poorly metabolised or excreted. The four processes happen simultaneously rather than in sequence, but it is far easier to learn them one at a time.

Diagram: The four processes of pharmacokinetics: absorption, distribution, metabolism and excretion.

Why Pharmacokinetics Matters in Practice

Prescribing errors are common. A review of English general practice records found a prescribing or monitoring error in 4.9% of prescription items, about 1 in 20. A systematic review of hospital inpatients found a median error rate of 7% of medication orders. The consequences range from minor inconvenience to fatal toxicity. Many of these errors involve pharmacokinetic considerations. One example is a dose too large for the patient's renal function. Another is a drug that interacts with another by inducing a liver enzyme (making the liver produce more of that enzyme). A third is a dosing frequency that does not match the half-life. The British National Formulary (BNF) and NICE guidance both lean heavily on pharmacokinetic principles when they recommend particular doses, intervals and monitoring strategies.

Several patient factors routinely change pharmacokinetics and need to be considered before any drug is prescribed:

• Renal function, particularly important for water-soluble drugs cleared by the kidneys (e.g. gentamicin, digoxin, lithium). See Glomerular Filtration Rate and the Measurement of Kidney Function.
• Hepatic function: relevant for drugs that undergo extensive hepatic metabolism (e.g. warfarin, opioids such as morphine, and statins, which lower cholesterol). See Hepatic, Biliary and Pancreatic Pathology.
• Age: neonates (newborn babies) and the elderly handle drugs differently to younger adults.
• Pregnancy: fluid balance, plasma protein levels and renal blood flow all change.
• Other medicines taken at the same time (concomitant medication): many of the most important drug-drug interactions are pharmacokinetic in nature, although pharmacodynamic interactions are also common.
• Acute illness: fever (pyrexia), sepsis and shock can all alter absorption, distribution and clearance.

Absorption

Absorption is the process by which a drug crosses the membranes between its site of administration and the systemic circulation. The route of administration largely determines how completely, and how quickly, this happens. The principles of how molecules cross cell membranes are covered in Biological Membranes.

Routes of Administration

Routes are broadly divided into enteral (via the gastrointestinal tract, which begins at the mouth) and parenteral (everything else).

Enteral routes:

• Oral (PO): the most common route. Convenient, cheap and safe, but absorption is slow, variable and exposed to first-pass metabolism. Most absorption occurs in the small intestine, the anatomy of which is described in Anatomy and Physiology of the Midgut.
• Sublingual / buccal (under the tongue / between the cheek and gum): drug is absorbed across the oral mucosa directly into the systemic circulation, bypassing the liver. Useful for drugs that would otherwise be heavily metabolised on first pass (e.g. glyceryl trinitrate).
• Rectal (PR): absorbed via the haemorrhoidal veins (the veins of the rectum). The lower rectum drains directly into the systemic circulation, so the drug partly bypasses the liver. Useful when a patient cannot swallow or is vomiting (e.g. diclofenac, paracetamol, diazepam).

Parenteral routes:

• Intravenous (IV): drug is delivered straight into the bloodstream, giving a rapid onset and 100% bioavailability.
• Intramuscular (IM) and subcutaneous (SC): slower than IV; absorption depends on local blood flow.
• Inhaled: the large surface area of the lungs allows fast absorption. It suits drugs intended to act locally on the airways (salbutamol) or systemically (volatile anaesthetics, which are anaesthetic gases and vapours).
• Transdermal: patches give slow, sustained release through the skin (fentanyl, oestrogen, nicotine).
• Topical: applied to skin or mucosa for local effect.
• Intrathecal / epidural: injected directly into the cerebrospinal fluid or epidural space, used for spinal anaesthesia and selected chemotherapy.

Bioavailability

Bioavailability, denoted F, is the fraction of an administered dose that reaches the systemic circulation in an unchanged form. By convention an intravenous dose has a bioavailability of 1 (or 100%), and bioavailability for any other route is expressed relative to IV.

Several factors reduce oral bioavailability:

• Formulation: modified-release tablets (which release the drug slowly), enteric coatings (coatings that resist stomach acid) and excipients (the inactive ingredients in a tablet) all alter dissolution.
• Gastric emptying and pH: affected by food, antacids and drugs that slow gastric motility (the muscle movements that empty the stomach).
• Food interactions: chelation (binding of the drug to metal ions) of tetracyclines and quinolones with calcium and iron is a classic example.
• Disease of the gut: vomiting, malabsorption (poor absorption from the gut, as in Crohn's disease, coeliac disease and short-bowel syndrome) and gut wall oedema in heart failure all reduce absorption.
• First-pass metabolism: see below.

Diagram: Plasma concentration-time curves following an intravenous and an oral dose of the same drug. Bioavailability (F) is the ratio of the oral area under the curve (AUC) to the intravenous AUC, when the same dose is given by each route.

First-Pass Metabolism

Drugs absorbed from the small intestine are carried in the hepatic portal vein to the liver before they reach the systemic circulation. The liver is the body's main metabolic organ and may extract and inactivate a substantial fraction of an oral dose on its very first pass. The gut wall also limits how much of an oral dose reaches the blood. It contains the enzyme CYP3A4 (a cytochrome P450 enzyme, described in the P450 section below), which metabolises some of the drug. It also contains the efflux pump P-glycoprotein (a transporter protein that pumps absorbed drug back into the gut).

Drugs with extensive first-pass metabolism include:

• Glyceryl trinitrate (GTN): virtually all of an oral dose is destroyed by first pass, which is why it is given sublingually or transdermally.
• Propranolol: oral bioavailability is around 25%.
• Morphine: oral bioavailability is around 30%, so oral doses are larger than parenteral doses. When converting from oral to subcutaneous or intravenous morphine, the BNF uses a ratio of 2:1 (for example, 10 mg by mouth is roughly equivalent to 5 mg by injection).
• Lidocaine: first-pass metabolism is so extensive that lidocaine is not given by mouth to produce effects elsewhere in the body. Lidocaine preparations applied to the mouth and gums act locally instead.

Routes that bypass first pass include intravenous, intramuscular, subcutaneous, inhaled, sublingual, buccal and transdermal administration. Rectal administration bypasses first pass only partly, because the upper rectum drains into the portal vein.

Diagram: The hepatic portal vein system. Orally absorbed drugs are carried via the portal circulation to the liver, where first-pass metabolism may inactivate a large fraction of the dose before it reaches the systemic circulation.

Creative commons source by OpenStax College, CC BY 3.0.

Distribution

Once a drug reaches the systemic circulation, it is distributed around the body. Distribution is governed by three things: how well the drug crosses capillary walls, how readily it dissolves in different tissues, and how much of it is bound to plasma proteins.

A few general rules:

• Lipophilic (fat-soluble) drugs cross cell membranes easily and reach the central nervous system, adipose tissue (body fat) and other deep compartments.
• Hydrophilic (water-soluble) drugs stay in the extracellular fluid (the fluid outside cells) and need gaps between cells or transporters to leave the bloodstream.
• Highly perfused tissues (brain, liver, kidneys, heart) reach equilibrium with the blood quickly; poorly perfused tissues (fat, bone) take much longer.

Volume of Distribution

The volume of distribution (V_d) is a theoretical volume; it is the volume of fluid into which a drug would have to be dissolved to give the plasma concentration that is actually measured. The relationship is:

V_d  =  Dose  ÷  C₀   (C₀ = plasma concentration immediately after an IV bolus, a single quick injection into a vein)

V_d is best understood by reference to a few benchmark numbers in a 70 kg adult:

• Plasma volume is around 3 L.
• Extracellular fluid is around 14 L.
• Total body water is around 42 L.

A drug with a V_d close to plasma volume (around 3 L) is essentially confined to the bloodstream. Heparin is a good example. It is a large polar molecule (a large, charged, water-loving one), so it cannot leave the vasculature (the blood vessels). A drug with a low V_d only slightly above plasma volume is one that distributes a little further but is held in the circulation by tight protein binding. Warfarin, with a V_d of around 8-10 L, falls into this group. At the other extreme, a drug with a V_d much greater than total body water has moved out of the blood and is stored in the tissues, most often in fat, muscle or cell membranes (membrane phospholipids). Digoxin has a V_d of around 500 L, and amiodarone even more.

A useful clinical implication: the larger the V_d, the larger the loading dose required to achieve a given plasma concentration. A loading dose is a large first dose that brings the plasma concentration up quickly. A drug with a large V_d also lingers for longer after the last dose.

Plasma Protein Binding

Many drugs travel in the blood reversibly bound to plasma proteins, principally albumin (which binds acidic and neutral drugs) and α₁-acid glycoprotein (a second plasma protein, which binds basic drugs). The structural reasons these proteins are such effective drug carriers are covered in Structure of Proteins. Only the free, unbound fraction is pharmacologically active and available for metabolism and excretion.

Protein binding becomes clinically important when all three of the following are true:

• The drug is highly protein bound (greater than 90%).
• The drug has a narrow therapeutic index (a small gap between a useful dose and a toxic dose).
• The drug has a low volume of distribution.

Warfarin, phenytoin and sulphonylureas are classic examples. If a second highly protein-bound drug displaces the first from albumin, the free fraction rises and a previously stable dose can become toxic. Displacement is often given as the textbook explanation for the warfarin-NSAID (non-steroidal anti-inflammatory drug) interaction. The BNF entry for ibuprofen and warfarin does not mention displacement. It rates the interaction severe because both drugs can increase the risk of bleeding.

Conditions that reduce albumin include pregnancy, nephrotic syndrome (a kidney disease in which protein is lost in the urine), malnutrition, advanced liver disease and severe burns. They increase the free fraction of bound drugs and predispose to toxicity at apparently normal total drug concentrations.

Metabolism

Most drugs are fat-soluble (lipid-soluble). That lets them enter cells, but it also lets the kidneys reabsorb them from the renal tubule. Metabolism is the process of converting drugs to more water-soluble forms that the kidneys can excrete. The liver is by far the most important metabolic organ, although the gut wall, lung and kidneys all make a contribution. The general principles of how enzymes are regulated are covered in Enzymes and Regulation of Protein Function.

Metabolism is conventionally divided into Phase I and Phase II reactions. Most drugs undergo Phase I followed by Phase II, but either may occur alone, and a small number of drugs are excreted unchanged.

Phase I Reactions

Phase I reactions introduce or unmask a polar functional group (a reactive chemical part of the molecule) on the drug molecule, usually by oxidation, reduction or hydrolysis (splitting a bond using water). The product is a metabolite (a product of metabolism) that is more water-soluble and, in most cases, less pharmacologically active than the parent drug.

There are three useful exceptions to remember:

• Pro-drugs are inactive until metabolised. For example, codeine is converted to morphine, levodopa is converted to dopamine, and enalapril is converted to enalaprilat.
• Some drugs have active metabolites that contribute to or prolong the effect of the parent drug. For example, diazepam is converted to nordiazepam.
• Some drugs are converted to toxic metabolites. For example, paracetamol is converted to NAPQI (N-acetyl-p-benzoquinone imine, a toxic by-product), which is responsible for liver damage (hepatotoxicity) in overdose.

Phase II Reactions

Phase II reactions conjugate the drug or its Phase I metabolite. That means the body attaches one of its own molecules (an endogenous molecule) to the drug, producing a highly water-soluble compound that is readily excreted in bile or urine. The main reactions differ in which molecule is attached:

• Glucuronidation: attaches glucuronic acid (the commonest reaction, catalysed by UGT enzymes, short for UDP-glucuronosyltransferase)
• Sulphation: attaches a sulphate group
• Acetylation: attaches an acetyl group (genetic variation makes some people fast acetylators and others slow acetylators: slow acetylators build up more of drugs such as isoniazid and hydralazine)
• Methylation: attaches a methyl group
• Glutathione conjugation: attaches glutathione (the pathway that mops up NAPQI in paracetamol metabolism, until it is overwhelmed in overdose)

The Cytochrome P450 System

The cytochrome P450 (CYP) family is responsible for the great majority of Phase I oxidations. There are over 50 CYP enzymes in humans, but a handful do most of the drug-metabolism work, and three in particular matter most in practice:

• CYP3A4: metabolises an estimated 30 to 50% of the drugs in clinical use, including statins (cholesterol-lowering drugs), calcium channel blockers, macrolides (a class of antibiotic) and many opioids (morphine-type painkillers). It is also expressed in the gut wall, where it contributes to first-pass metabolism.
• CYP2D6: metabolises tricyclic antidepressants (an older group of antidepressants), many selective serotonin reuptake inhibitors (SSRIs), beta-blockers, codeine and tamoxifen. Its activity varies markedly between individuals. About 7 to 10% of people of European ancestry are poor metabolisers with a non-functional gene. Ultra-rapid metabolisers carry duplicated copies of the gene. They are more common in Spain, Italy, Greece, Africa and the Middle East than in northern Europe. Ultra-rapid metabolisers can develop morphine toxicity from standard codeine doses.
• CYP2C9: metabolises warfarin, phenytoin and many NSAIDs.

Genetic variation in CYP enzymes is a topic in its own right and is covered more fully in the SimpleMed article on pharmacovigilance (monitoring the safety of medicines once they are in use) and pharmacogenetics (how a person's genes affect their response to drugs).

Enzyme Induction and Inhibition

CYP enzymes can be induced (the body makes more of the enzyme, which increases metabolism) or inhibited (their activity is blocked, reducing metabolism). The clinical consequences are opposite: inducers reduce the plasma concentration of co-administered drugs and risk loss of efficacy, while inhibitors raise plasma concentrations and risk toxicity.

A useful memory aid for the common CYP inducers is PC BRAS. The first letters of the inducers below spell it:

• P: Phenytoin
• C: Carbamazepine
• B: Barbiturates
• R: Rifampicin
• A: Alcohol (chronic use)
• S: St John's wort, Smoking

A matching aid for the common CYP inhibitors is AO DEVICES. Again, the first letters of the inhibitors below spell it:

• A: Allopurinol (mainly a xanthine oxidase inhibitor, an enzyme outside the CYP family, but it still alters the metabolism of azathioprine and mercaptopurine), Amiodarone
• O: Omeprazole
• D: Disulfiram
• E: Erythromycin and clarithromycin (macrolide antibiotics, of which clarithromycin is the stronger CYP3A4 inhibitor)
• V: Valproate
• I: Isoniazid
• C: Ciprofloxacin, Cimetidine
• E: Ethanol (acute use)
• S: Sulphonamides, Some SSRIs (fluoxetine, paroxetine), Grapefruit juice

The grapefruit juice example is worth singling out. A single glass irreversibly inactivates part of the CYP3A4 in the gut wall. The effect lasts until the body makes new enzyme. It is still measurable 24 hours after a single glass. It can substantially raise plasma levels of simvastatin, ciclosporin, felodipine and several others. (The interaction with amlodipine is much weaker than with felodipine, despite both being dihydropyridines, a class of calcium channel blockers.)

Induction takes days to weeks to develop because new enzyme has to be synthesised; inhibition is usually immediate.

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