Drug Metabolism and Excretion L4 Flashcards
Drug Elimination
… is the irreversible removal of drug from the body
- Metabolism (biotransformation) – primarily the role of liver
- Excretion of unchanged drug: primarily the role of kidney (for polar molecules), but may be cleared be expiration (for volatile molecules) or through the gut.
- Most drugs eliminated by a combination of routes
Metabolism
Metabolism is carried out by enzymes, and can take place anywhere in the body. However, the vast majority of small molecule drugs are metabolised in the liver. The commonest method of metabolism is a 2-phase process involving:
Phase 1 (Modification):
Commonly involves a cytochrome P450-dependent mixed-function oxidase.
Commonly causes an oxidation, reduction or hydrolysis.
Creates highly-reactive compounds
Phase 2 (Conjugation): Joins (conjugates) the Phase 1 metabolite onto another molecule in order to make it charged. Such groups include: glutathione (GSH), sulfate, glycine, or glucuronic acid
Phase 1 - Modification
- cytochrome P450s (CYP) and mixed-function oxidases:
– important group of haem containing enzymes
– metabolise a wide range of different molecules
– important site of drug interactions, through substrate inhibition, non-substrate inhibition, and induction - Commonly causes an oxidation, reduction or hydrolysis.
- Creates highly-reactive compounds
- May involve other enzyme systems: eg. alcohol dehydrogenase, monoamine oxidase
Phase 2 - Conjugation
Joins (conjugates) the Phase 1 metabolite onto another molecule in order to make it charged. Such groups include:
- glutathione (GSH)
- sulfate
- Glycine (glycyl)
- glucuronic acid (glucoronyl): hence glucuronidation
One effect of adding a net charge to a metabolite is in order to aid renal clearance (excretion).
Active Metabolites
Just because a drug is no longer present, the effect of dosing may continue because metabolites may be active, and hence either toxic or therapeutic.
Examples:
- ‘Prodrugs’ (convert from inactive to active drug)
- Morphine (active, but converted to morphine-6-glucuronide, another analgesic)
- Pethidine (active, but converted to norpethidine, which is epileptogenic)
Excretion / Elimination
Routes for drugs and their metabolites are
1) Renal – particularly by filtration in the glomerulus and secretion in the proximal tubule
2) Hepatic/biliary and hence faecal or enterohepatic elimination
3) Other:
- Sweat
- Milk (a problem for lactating mothers)
- Breath (evaporation in the lungs)
Drug Elimination in the kidney
- About 20% of the plasma is filtered in the glomerus. Charged or polar molecules will then tend to be ‘trapped’ in the tubules, and hence lost in the urine
- Some drugs are actively secreted into the tubules, by two families of transporters:
- Acid transporters (for penicillin, uric acid, …)
- Organic base transporters (for pethidine, quinine, …)
- If drugs are secreted by the same transporter, they can compete and hence slow their excretion.
- Urine tends to be acidic, hence there can be ion trapping mediated by the pH.
quantifying the effect of metabolism or clearance
For the clearance of many drugs:
dC / dt = -kC^n
where C =Concentration in the Compartment,
k = a constant,
n = the ‘order’ of elimination of metabolism
so for first order , n = 1
first order kinetics
C = Cmax e^-kt
Half Life - the time taken for the drug concentration to fall to 1/2 of its initial value
C = Ae^-kt
substitute in C = 0.5A
0.5A = Ae^-kt0.5
ln(0.5) = -kt0.5
t 0.5 = ln(2) / k
first order result using our definition of half life
C = Cmax(0.5)^t/t0.5
zeroth order kinetics
dC/dt = -k
integrate
C = -kt + A
on a graph , where C is on the y axis and time(hours) is on the x axis
A = y intercept
slope = -k
common dosing regimes
- regular bolus dosing
- continuous IV infusion
regular boluses are often easier to give , but give less stable drug levels , meaning that its harder to stay in a tight therapeutic window
