interindividual variability in PK

Question 1

What factors lead to differences in enzyme expression

Answer 1

1. age
2. diet
   3.lifestyle (alcohol/smoking)
3. sex
4. pregnancy
5. genetic variations
6. ethnicity

Question 2

how does pregnancy effect pK between individuals

Answer 2

CYP enzyme levels may increase or decrease,
Body water and fat increases higher VD for lipophilic lower blood distribution
plasma proteins decrease, (albumin and AAG) more free drug more VD
increased progesterone reduces gastric emptying

Question 3

how does ethnicity effect pK between individuals

Answer 3

cultural and environmental factors can cause varying diets and weight variations. also varying allele frequencies between ethnic groups
example: poor metaboliser CYP2D6 more common in white populations than ultra metabolizer

phenotypes not exclusive to ethnic group but more common in some
ex: carriers of SLCO1B1 genes have impaired uptake and metabolism of statşns.

Question 4

how does genetics effect pK between individuals

Answer 4

allelic variation in CYP450 enzymes can lead to phenotypes:
1. poor metaboliser (two non functional alleles)
2. intermediate metaboliser (one reduced function allele)
3. extensive metaboliser (one functional allele)
4.ultra rapid metaboliser (multiple copies of functional allele)

ex: CYP2D6
poor metaboliser of codeine: no detectable morphine levels in blood (no analgesic efficacy)
ultra metaboliser: increased risk of respiratory depression

Question 5

how does sex effect pK between individuals

Answer 5

women generally have higher percentage of body fat and lower water content, transporter and metabolising enzyme activity varies

ex: theophylline half life higher in men (diff schedule of administration
propranolol clearance less in women (more potential side effx in women)
ethanol first pass metabolism higher in men less vd in women, increased blood conc in women. ,
absorption of iron higher in women

lipophilic drug (opioid benzodiapine) higher vd in women lower in blood.

CYP2D6 activity higher in women

Question 6

how does lifestyle effect pK between individuals

Answer 6

smoking (increases metabolic activity of enzymes) ex: increased activity of CYP1A2, increased clearance of antipsychotics
alcohol (effects on gastric emptying and metabolism, can induce or inhibit CYP2E1 has effects on paracetamol metabolism)

Question 7

how does age effect pK between individuals

Answer 7

plasma proteins lower in neonates (higher drug distribution)

fat distribution changes with age (hydrophilic drugs have lower distribution and shorter half life with age, lipophilic drugs have higher distribution and half life with aging as fat increases water decreases)

diff metabolizing activity of same enzyme (CYP3A4 activity low in neonates and elderly, higher in the middle)

Question 8

how does diet effect pK between individuals

Answer 8

could prolong gastric emptying, decreases absorption. ex: sometimes slower in vegetarians
interactions inhibit or induce enzymes ex: CYP3A4 inhibited by grapefruit. increased bioavailability and decreased clearance and half life of drugs metabolized by this enzyme)

Question 9

what is pharmacogenetics and pharmacogenomics

Answer 9

study of how a single gene influences variability in drug response

study of how a genetic differences in multiple genes influence variability in drug response

differences relate to transporters and metabolizing enzymes