Pharmacokinetics II: drug metabolism and elimination Flashcards
biotransformation
transformation of a molecule itself as its moving through the body.
these are chemical modifications made by an organism on a chemical compound.
metabolic enzymes
aim is make drug less lipophilic and more hydrophobic
favoured method of elimination
urine and/or bile
phases of drug metabolism
2 phase process:
phase I:
functionalisation
phase II:
conjugation
Phase I: functionalisation
is the addition of functional groups to make the drug more chemically reactive to prepare the drug for phase II reactions.
includes:
oxidation, reduction, hydrolysis, hydration
Phase II: conjugation
linking together where drug is coupled to a second relatively larger water soluble molecule that increases water solubility.
this makes the drug less able to diffuse across membranes and favours its elimination.
includes: glucuronidation (glucaronic acid is added) sulfation acetylation glutathione conjugation
enzymes = transferases add these molecules onto the drug
oxidation (phase I)
enzyme = CYP 450 and its isoforms a.k.a. microsomal enzymes or cytosolic enzymes are also capable of oxidating
add an - OH group
occurs in the ER
e.g. phenytoin gets oxidised at the fourth position to 4 hydroxyphenytoin
other examples of cytosol enzymes:
alcohol dehydrogenase converts ethanol to acetyl aldehyde
aldehyde dehydrogenase converts acetyl aldehyde into acetic acid
reduction (phase I)
reductases in gut
CYP 450 can also reduce but in the presence of low oxygen.
e.g. aldehydes and ketones are reduced to alcohols.
warfarin (ketone) is reduced to alcohol.
chloral hydrate (anaesthetic) is reduced to trichloroethanal (active)
hydrolysis (phase I)
mainly cytosolic enzymes
e.g.
esterase enzymes removing ester group
amidase enzymes removing amide group
esterase enzymes e.g. aspirin where acetyl group is removed leaving salicylic acid (which is the functional and active component)
glucuronidation (phase II)
conjugation reaction in the ER of microsomes.
addition of a UDP glucuronic acid
enzyme = glucuronyl transferase
results in: a conjugate that is more water soluble and has a glucuronic acid moiety that cannot readily pass through membranes so its elimination is favoured.
e.g.
paracetamol undergoes full transformation to inactive conjugate
salicylic acid (from aspirin) is transformed into inactive conjugate
morphine is transformed into less active conjugate morphine 6 glucoronide
4 hydroxyphenytoin is transformed into inactive conjugate.
CYP 2D6 isoform
is the isoform which is famous for polymorphisms in individuals
CYP 450 monooxidation
along with NADPH P450 reductase enzyme (electron donor) it transfers one oxygen molecule onto drug making it more reactive and oxidized.
sulfation (phase II)
addition of sulfate moiety
occurs in: cytosol
enzyme: sulfotransferases
examples:
paracetamol can undergo conjugation to inactive form
tamoxifen sulfation conjugation to inactive form
glutathione (GSH) conjugation (phase II)
glutathione = tripeptide
glutamine
cysteine
glycine
enzyme: glutathione S transferase
location: cytosol, microsomes (ER) + mitochondria
example:
toxic metabolite of paracetamol when in saturation state is eliminated in liver by glutathione conjugation (NAPQI)
first pass metabolism
includes both the GI tract and the liver.
NOTE: hepatic portal vein is considered pre systemic.
prodrugs
inactive drug with metabolites as the functional group
azathioprine is inactive but when converted to mercaptopurrine it forms an active metabolite.
3 methlymorphine (codeine) is inactive pro drug but when converted to morphine it forms an active metabolite
active drugs with active metabolites
diazepam (valium) is an active drug but its metabolites from phase I reactions are also active:
nordiazepam
oxazepam
Renal drug elimination
3 steps:
- filtration @glomerulus
only small molecules < 20 kDaltons and they must be free drugs.
i.e. drugs bound to plasma proteins will not be filtered here.
20% of renal plasma flow is filtered here. - Active transport @ proximal tubule
can transport molecules against concentration gradient using non selective membrane ion carriers:
These include OATs and OCTs.
plasma bound drugs can be filtered here.
BUT the ion carriers can become saturated. - Diffusion + reabsorption @distal tubules
where drug concentration is higher in glomerular filtrate than the distal tubules, the drug can diffuse and get reabsorbed back into the blood.
BUT: the drug needs to be lipid soluble and in the unionised state for it to become reabsorbed
OATs and OCTs
OATs = organic anion transporters which transport acidic drugs such as penicillin.
OCTs = organic cation transporters which transport basic and drugs in the ionised state as well in the ionised state.
urinary drug/metabolite excretion
altering pH of urine will alter the concentrations of the drug being eliminated.
Recall: drugs that are ionised will not be reabsorbed back.
overdose of phenobarbital (weak acid) can be overcome by infusing with sodium bicarbonate which will ionise the drug favouring its elimination.
drug elimination billiary system
drugs can be eliminated directly into bile ducts from the liver and eliminated out through the faeces.
large drugs > 300 Daltons are transported this way e.g. rifampcin
gut microflora drug conversion
can metabolise drugs and convert them to more lipophilic compounds by removing any conjugates that have been added to the compounds.
enzymes:
bacteria synthase and beta glucuronidases
the drug can then get reabsorbed back into the hepatic portal vein
problems:
half life of drug is increased
hepatic exposure is increased
could potentially lead to the formation of toxic metabolites.
disposition
compound moving between compartments by rapid equilibrium and diffusion
rate of drug movement
characterised by steady rate constants:
rate of absorption x rate of elimination
first order kinetics or linear kinetics
is exponential @ plasma conc vs time
is linear @ log plasma conc vs time
does not saturate and rate of elimination is proportional to drug concentration i.e. increase in drug concentration causes increase in drug metabolism to avoid accumulation.
repeated dosing concerns:
dosing interval vs half life
half life is the same for drugs at full dose or half dose i.e. not variable.
zero order kinetics or non linear kinetics
is linear @ plasma conc vs time
is non linear @ log plasma vs time
elimination rate saturates with higher drug concentration
elimination is independent of initial drug concentration i.e. high concentration does not influence how quickly metabolised.
half life is dependent on dose so always variable.
