16A20: Exam Report

Outline the role of the liver in drug pharmacokinetics.

62% of candidates passed this question.

Most candidates structured their answer to this question well – they were aware of first pass metabolism and the effect of protein synthesis upon volume of distribution of drugs. Knowledge concerning Phase I and Phase II reactions was frequently inadequate. Many candidates were aware that these processes as well as inactivating or activating drugs resulted in increased water solubility to aid excretion via bile or urine. Few candidates discussed the significance of the large blood flow to the liver or the implications of high and low extraction ratios especially in relation to liver blood flow.

Biv / 16A20: Outline the role of the liver in drug pharmacokinetics

First Pass Metabolism

Definition = proportion of drug absorbed, delivered to liver by Portal Circulation & metabolised before reaching systemic circulation

  • Influence amount of drug which becomes available

→ BIOAVAILABILITY = 1 – 1st pass metabolism

Plasma Protein Binding

  • Drugs bind reversibly to proteins for transport

→ Albumin, α1 glycoprotein, lipoproteins

  • Liver synthesises plasma proteins


    • Vd – inversely proportional; ↑PPB = stays in plasma
    • t ½ – only free drug is active; bound portion acts as reservoir
    • Clearance – unbound drug is metabolised


  • Hepatic metabolism of drugs can:
    1. Metabolise drugs into exactable products
    2. Metabolise prodrugs into active molecules e. enalapril

2 phases of metabolism

Phase I

  • Non-synthetic
  • Introduces/unmasks a polar molecule
  • ↓/↑/unalter pharmacological activity
  • Oxidation → most common
    • Add O2/remove hydrogen
    • Dealkylation, hydroxylation, deamination, desulphuration
    • Most via CYP450
    • Most CYP450 enzyme located in liver

Phase II

  • Synthetic
  • Adds sugar = ↑size & polarity
  • Allows drug excretion in urine/bile
  •  Conjugation reactions:

Hepatic Clearance

Hepatic clearance = HER + HBF

  • Hepatic extraction ratio = % of drug removed by plasma on each pass through the liver

HER = 1 – bioavailability

  • Depends on Intrinsic Clearance & PPB
  • Intrinsic clearance = hepatic metabolism of drugs if unlimited & all drug was unbound
  • High intrinsic clearance (lignocaine, M, propranolol)
    • Almost all drug presented to liver removed
    • ∴limited by HBF
  • Low intrinsic clearance (warfarin, diazepam)
    • Liver already maximally metabolising
    • ∴limited by enzyme activity
  • PPB → only unbound drug can be metabolised
    • High IC → ∆ PPB has maximal effect on clearance
    • Low IC → ∆ PPB has significant effect on clearance
  • Hepatic BF →↑BF = ↑drug presented for metabolism per unit time
    • High IC = ↑BF = ↑Clearance
    • Low IC = ↑BF = not much ∆ clearance