STAMP week 4 –

Excretion and
pharmacokinetic variation
SAM BARNES
Excretion
Elimination refers to the removal of a drug from the plasma

Excretion refers to the removal of the drug from the body

Main mechanisms are biliary and renal

 At the glomerulus

• Small, non-protein bound, water soluble

molecules filtered
• Glomerular filtration barrier resistant to protein
therefore protein bound drugs not excreted here

Renal excretion
1 In the PCT

• Energy-requiring processes to actively secrete

drug into tubule
• As roughly only 20% of renal blood flow is
filtered, many drugs are secreted here after
bypassing the glomerulus
• ACEi, penicillin
 In the DCT
• Passive diffusion from luminal cells into tubule
• Urine pH then affects rate of excretion of acidic and basic
drugs

For acidic drugs

Renal excretion • Alkaline urine leads to ionisation (where pH>pK)
• Less lipid soluble and therefore less tubular reabsorption
2
For basic drugs
• Acidic urine leads to ionisation (where pH<pK)
• Also limits reabsorption and favours excretion

Relevance
• Use of bicarb to alkalinise the urine in salicylate overdose
 High molecular weight compounds are excreted in bile
◦ Muscle relaxants

Biliary Energy required to pump from low to high concentrations

from hepatocyte into biliary tree
excretion
Some drugs excreted unchanged (rifampicin), some excreted
in conjugated form e.g. morphine-6-glucuronide
 Hoffman degradation
◦ Describes the metabolism of an amide to an amine with one
fewer carbon atom
Non-enzymatic ◦ Key example is atracurium

elimination Atracurium
◦ Undergoes both ester hydrolysis by plasma esterases (minor
component)
and spontaneous Hoffman degradation (major component)
Genetic polymorphisms
CYP450 enzymes

Key enzymes involved in phase 1 metabolism and also in

extrahepatic processes in the kidney and gut wall

Poor metabolism
Polymorphisms can lead to: Rapid metabolism
Ultra-rapid metabolism
CYP450 example
CYP2D6
◦ Poor metabolisers: 10% Caucasians. Codeine not metabolised into morphine and therefore minimal
effect.
◦ Ultra-metabolisers: 30% Ethiopians. Anti-depressants rapidly cleared and therefore ineffective.
Plasma cholinesterase
Suxamethonium undergoes hydrolysis in the plasma, catalysed by plasma
cholinesterase
◦ Also mivacurium

Autosomal recessive inheritance of atypical variant

◦ Carried on chromosome 3 Acetylcholine
◦ Forms are Ea (atypical), Es (silent) and Ef (Fluoride resistant)

Leads to failure to metabolise and subsequent suxamethonium apnoea

Different alleles lead to different durations of block

◦ Ea/Eu: 30 mins
◦ Es:Es: >3 hours Suxamethonium
Dibucaine number
Technique by which the presence of an atypical cholinesterase gene can be identified

Substrate called benzylcholine mixed with cholinesterases and metabolised

Normally this leads to the emission of light, which can be detected and the wavelength measured

Adding the local anaesthetic dibucaine inhibits normal cholinesterase, but not atypical

The amount of light emitted after the addition of dibucaine allows an interpretation of the type of cholinesterase
◦ Ongoing light emission  cholinesterase not inhibited  atypical
◦ Reduced light emission  cholinesterase inhibited  probably normal
Acetylation
N-acetyltransferase is controlled by genes NAT1 and NAT2, which creates fast and slow
acetylators dependent on expression

Fast acetylators: Clear isoniazid rapidly, less response

Slow acetylators: More side effects e.g. procainamide