genetic determinants of pharmacokinetic variability

variable response across populations

same diagnosis, same drug, same dose →

• drug effective and harmful

• drug not effective and harmful

• drug effective and not harmful

• drug not effective and not harmful

other factors that influence treatment

ethnicity

age - fat distribution is different at different ages

pregnancy - cardiac output is increased, higher filtration rate (drug eliminated at a faster rate), fat distribution is different

disease

drug/food interactions - grapefruit interacts with CYP3A4 → increase in metabolism

PK/PD interactions

genetic variation

pharmacogenetics

the effect of genetic variants on the response to drugs

normally focused on a single drug, single gene and/or single drug response

pharmacogenomics

the effect of the persons genome on response to drugs

normally looks at the entire genome of an individual, taking into consideration the combined effect of multiple variants and multiple drugs

drug variability

therapeutic window - the range of drug concentrations in the blood that provides effective treatment without causing toxicity

e.g. drugs with a narrow therapeutic index, its hard to find a balance where the drug can cause therapeutic effect and not cause toxicity

reasons for drug variability

patient genetic variability can influence how the individual responds to certain treatment

pharmacokinetics: ADME

pharmacodynamics: receptors, ion channels, enzymes

ADME

absorption: how the drug gets into the body and circulation

distribution: how the drug is dispersed throughout the body

metabolism: how the drug is transformed (activated or inactivated)

excretion: how the drug is removed from the body

control of ADME

transporters are key for the absorption, distribution and excretion of drugs

transport drugs across biological membranes using wither ion gradients or ATP

key in the bowel, kidneys, BBB and liver (and placenta in pregnacy)

• ATP binding cassette (ABC)

• solute carrier proteins (SLC) - OCTs and OATs

prone to genetic variation

e.g. ABCB1 - produces P-gp, transports loads of hydrophobic substrates

metabolism

phase 1 - functionalisation reactions (CYP450), introduces a functional group on the drug to make it more polar and prepared it for phase 2

phase 2 - conjugation reactions, attaches polar group to increase water solubility for excretion

cytochromes

mostly found in the liver

process around 75% of drugs

have a haem-iron group at the active site

can be affected by loss of function and gain of function mutations

how cytochromes work (phase 1)

drug binding → haem iron is reduced from 3+ to 2+ by electrons, oxygen binds which activates it → oxygen splitting and transfer, one oxygen atom is inserted into the substrate and the other is reduced to water → product release, oxidised product is released and the enzyme returns to its resting state

codeine

morphine prodrug, activated by CYP2D6 enzyme

used to treat mild-moderate pain

MOA: decreasing pre-synaptic release of neurotransmitters → decreasing post-synaptic neuronal excitability → promoting descending inhibition

CYP2D6 gene is highly polymorphic e.g. missense and frameshift mutations → variations in activity

phenytoin

anti-epileptic drug

narrow therapeutic window

metabolism carried out by CYP2C9 and CYP2C19 - has two missense polymorphisms that reduce metabolism

phase 2 enzymes

UGTs - glucuronidation

SULTs - sulphation

DPYD - dihydro group to pyrimidines

GSTs - glutathione

NATs - acetylation

TPMT - methylation

5-fluorouracil

chemotherapeutic used to treat many cancers

anti-metabolite - resemble natural metabolites and interfere with DNA or RNA synthesis by inhibiting thymidylate synthase (TS)

sometimes cause severe side effects due to toxic build up of the drug in the blood

metabolism - inactivated by phase 2 enzyme DPD

affected individuals had functional variants int he gene that resulted in formation of inactive or decreased functional protein

irinotecan

topoisomerase 1 inhibitor used to treat colorectal and pancreatic cancer

prodrug that is converted to its active metabolite, SN-38

SN38 is inactivated by UGT enzyme encoded by the UGT1A1 gene

most common variant is an insertion mutation → reduced gene transcription and activity → irinotecan toxicity as the active metabolite cannot be cleared

genetic variability - pharmacodynamics (trastuzumab)

HER2+ RTK amplification in breast cancer → increased cancer cell proliferation, growth and survival via amplification of MAPK and PI3K/Akt signalling pathways

challenges with pharmacogenetic profiling

ethnic variations

cost

availability of testing

drug type