Pharmacokinetics Part 2 – Distribution, Metabolism & Excretion (DME)

Distribution

Distribution is the process by which a drug is distributed from the plasma into body tissues. 

• Volume of distribution (Vd): the theoretical volume that would contain the total amount at the same concentration that it is observed in the blood plasma. 
• Essentially the Vd represents the degree to which a drug is distributed in tissues rather than plasma. 
  • High Vd → wide tissue distribution
  • Low Vd → confined mainly to plasma.

Plasma protein binding 

Plasma protein binding of drugs can affect drug distribution; drugs may bind proteins (e.g. albumin). Only the unbound (“free”) fraction is pharmacologically active.

• Example: phenytoin is 90% albumin-bound; changes in albumin levels can affect free phenytoin levels. 
• Other highly protein-bound drugs include: fluoxetine, verapamil, warfarin, amiodarone

Blood brain barrier

Distribution of drugs across the blood brain barrier also affects the action of drugs; only drugs which are small and lipophilic are able to cross. 

• Example: morphine is an agonist at μ receptors in the brain eliciting an analgesic effect, and in the gut causing constipation. Loperamide is a μ receptor agonist but does not cross the blood brain barrier, therefore causes constipation without an analgesic effect. 

Metabolism

Metabolism is the enzymatic breakdown of drugs, mainly in the liver.

• Usually produces inactive metabolites.
• Some drugs are prodrugs, activated by metabolism (e.g. clopidogrel).
• Metabolism generally increases water solubility and polarity, to prepare the drug for excretion 

One of the most important enzymes in metabolism is CYP450, which catalyses oxidation of several drugs and is responsible for many clinically significant drug interactions. CYP450 enzymes can be induced or inhibited by several drugs, resulting in several clinically significant drug interactions.

Created in BioRender. Boucher, M. (2025) https://BioRender.com/e2uqnxw

Fig 1: Inhibitors and inducers of CYP450

Excretion

Excretion is the removal of drug and metabolites from the body

• Water soluble compounds are usually renally excreted through urine
• Lipophilic drugs with high molecular weights are not usually reabsorbed through the GI tract, therefore are excreted through the biliary system through faeces 

Patient characteristics affect the excretion of drugs. Patients with poor renal function will have reduced renal excretion of drugs which may lead to accumulation of the drug and dosage adjustments may be required. 

Elimination half-life t½.

Elimination half life describes the time it takes for the plasma concentration of the drug to halve in value and is denoted by the symbol t½. The elimination half life of a drug indicates how long it circulates in the body for. 

• Example: amiodarone has a long half life (~50 days), which means that occasionally missed doses are unlikely to affect the patient. Drugs with long half lives like amiodarone often require a loading dose followed by a maintenance dose; the loading doses aim to achieve therapeutic levels quickly and the maintenance dose aims to maintain the response. 
• Example: naloxone has a short half life (~60-90 minutes) and may require additional doses for reversal of opioid toxicity.  

Pharmacokinetic definitions 

AUC (area under the curve): total drug exposure against time. 

• Reflects bioavailability and clearance of the drug.
• Reflects the actual body exposure to the drug after administration e.g. higher AUC means higher exposure to the drug. 

Cmax: Maximum plasma concentration after administration.

Tmax: Time at which Cmax is reached.

References 

1. Spc Clindamycin 150 mg Capsules Last updated on emc: 14 May 2024 Accessed 11/8/2024 Clindamycin 150 mg Capsules – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
2. SPC Morphine sulfate 10mg/5ml Oral solution. Last updated on emc: 17 Oct 2023. accessed 11/8/2024 from: Morphine Sulfate 10mg/5ml Oral Solution – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)
3. ICH M9 guideline on biopharmaceutics classification system-based biowaivers. 10 Feb 2020. Available from: M9 Step 5 on biopharmaceutics classification system based biowaivers (europa.eu), accessed 11/8/2024
4. SPC Pentasa Suppositories 1g – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 3/9/24
5. SPC NALOXONE 400 microgram/ml solution for injection or infusion – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 5/9/24