Pharmacokinetics II: drug metabolism and elimination

Question 1

biotransformation

Answer 1

transformation of a molecule itself as its moving through the body.

these are chemical modifications made by an organism on a chemical compound.

Question 2

metabolic enzymes

Answer 2

aim is make drug less lipophilic and more hydrophobic

Question 3

favoured method of elimination

Answer 3

urine and/or bile

Question 4

phases of drug metabolism

Answer 4

2 phase process:
phase I:
functionalisation

phase II:
conjugation

Question 5

Phase I: functionalisation

Answer 5

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

Question 6

Phase II: conjugation

Answer 6

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

Question 7

oxidation (phase I)

Answer 7

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

Question 8

reduction (phase I)

Answer 8

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)

Question 9

hydrolysis (phase I)

Answer 9

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)

Question 10

glucuronidation (phase II)

Answer 10

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.

Question 11

CYP 2D6 isoform

Answer 11

is the isoform which is famous for polymorphisms in individuals

Question 12

CYP 450 monooxidation

Answer 12

along with NADPH P450 reductase enzyme (electron donor) it transfers one oxygen molecule onto drug making it more reactive and oxidized.

Question 13

sulfation (phase II)

Answer 13

addition of sulfate moiety

occurs in: cytosol

enzyme: sulfotransferases

examples:
paracetamol can undergo conjugation to inactive form
tamoxifen sulfation conjugation to inactive form

Question 14

glutathione (GSH) conjugation (phase II)

Answer 14

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)

Question 15

first pass metabolism

Answer 15

includes both the GI tract and the liver.

NOTE: hepatic portal vein is considered pre systemic.

Question 16

prodrugs

Answer 16

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

Question 17

active drugs with active metabolites

Answer 17

diazepam (valium) is an active drug but its metabolites from phase I reactions are also active:
nordiazepam
oxazepam

Question 18

Renal drug elimination

Answer 18

3 steps:

1. 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.
2. 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.
3. 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

Question 19

OATs and OCTs

Answer 19

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.

Question 20

urinary drug/metabolite excretion

Answer 20

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.

Question 21

drug elimination billiary system

Answer 21

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

Question 22

gut microflora drug conversion

Answer 22

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.

Question 23

disposition

Answer 23

compound moving between compartments by rapid equilibrium and diffusion

Question 24

rate of drug movement

Answer 24

characterised by steady rate constants:

rate of absorption x rate of elimination

Question 25

first order kinetics or linear kinetics

Answer 25

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.

Question 26

zero order kinetics or non linear kinetics

Answer 26

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.