Pharmacokinetics

Question 1

What are the solute carrier transporters?

Answer 1

OAT and OCT, non-selective, facilitative and secondary active transporters

Question 2

What are ABC transporters?

Answer 2

ATP binding cassettes, e.g. P glycoproteins

Question 3

What are P-glycoproteins?

Answer 3

P glycoprotein (P-gp) is an active transporter that protects the body from some harmful substances by transporting the substance out of the body or out of sensitive organs

Question 4

What happens when the P-glycoprotein is inhibited?

Answer 4

Drugs enter GIT cells to be absorbed, diffuse into the brain, less elimination via kidneys

Question 5

What happens when the P-glycoprotein is active?

Answer 5

Gut cells transport drugs into lumen
drugs leave brain
drugs enter kidney tubules

Question 6

Equation for volume of distribution

Answer 6

Vd = Ab/ Cp

Ab= dose, Cp= plasma concentration

Question 7

What are the 3 aspects of renal drug elimination?

Answer 7

• Glomerular filtration (urine)
• Tubular secretion (urine)
• Reabsorption (into plasma)

Question 8

What are phase 1 reactions?

Answer 8

Catabolic, functionalisation, oxidation, reduction, hydrolysis

Increase polarity and make drug more water soluble

Question 9

What are phase 2 reactions?

Answer 9

Anabolic, conjugation, combining with endogenous molecule (e.g. methyl, acetyl, glucuronyl) to make more water soluble

Question 10

Explain phase II drug metabolism

Answer 10

• occurs mainly in the liver
• metabolite is pharmacologically inactive, less lipid soluble, excreted into urine or into bile/ faeces
• enzymes are potentially saturable (OD consequences)
• not considered important for drug-drug interactions

Question 11

Explain phase I drug metabolism

Answer 11

Occurs in liver and other tissues (e.g. intestine)

• GI wall –> portal vein –> liver –> metabolising enzymes
• metabolites may be more active/ toxic (e.g. paracetemol –> toxic metabolite is inactivated by conjugation enzymes which can be used up in OD)
• Potential site for drug-drug interactions

Question 12

Phase 1 drug metabolising enzymes

Answer 12

• broad substrate specificity
• 1 enzyme may catalyse the metabolism of many diff drugs
• 1 drug may be metabolised by multiple enzymes/ isoenzymes

Question 13

What are Cytochrome p450s?

Answer 13

Liver drug metabolising enzymes usually microsomal- embedded in ER

• catalyse oxidative metabolism of a range of xenobiotics and endogenous substances
• 70% of drugs are metabolised by these
• main: CYP1, CYP2, CYP3

Question 14

How do Cytochrome p450s vary?

Answer 14

• amino acid sequence
• sensitivity to inhibitors and inducing agents
• substrate specificity

Question 15

What does the CYP450 reaction require?

Answer 15

O2, NADPH, NADPH-P450 reductase

Question 16

Caution when elimination involves enzymatic metabolism

Answer 16

metabolising enzymes
o are potentially saturable (therapeutic dose is close to saturable level)
o activity can be influenced by many factors
♣ genetics (variance in metabolism)
♣ other drugs (can inhibit/ induce)

Question 17

CYP450 inhibition

Answer 17

drug interactions via metabolising enzymes
- enzyme inhibition
o drugs metabolised by the same enzyme, if administered together will compete for the metabolising enzyme

Question 18

CYP450 induction

Answer 18

• enzyme induction
  o some drugs can increase activity/ levels of the enzymes that metabolise them (e.g. alcohol, barbiturates), tolerance increases (higher dose must be taken to have a higher effect)

Question 19

CYP450 other interactions

Answer 19

• interaction between drugs and “herbal” medicines (St Johns Wort- antidepressant, effective with less side effects but is good at inducing cytochrome p450 enzymes interferes with metabolism of other drugs) or food components (e.g. grapefruit juice inhibits cyp450 enzymes)
  inhibition of cyp2D6 reduced analgesic effect

Question 20

other routes for excretion of drugs

Answer 20

• lungs: can remove gases and volatile liquids (e.g. many general anaesthetics), alcohol (concentration in lungs is similar to concentration in plasma)
• sweat, saliva, mucous, tears & milk: can excrete small amounts of drugs (some in milk can be dangerous to infants)
• Gut: some drugs can be excreted via bile faeces
  o Potential for enterohepatic cycling

Question 21

Enterohepatic cycling

Answer 21

Conjugated metabolites can be de-conjugated in gut and reabsorbed but bacteria to extend drug stay in body

Question 22

Constant infusion

Answer 22

Administration curve is mirror image of elimination curve
- Constant by constant infusion (plasma concentration increases then steadies)
o Steadied off due to elimination occurring
o Drug stopped: falls down (elimination)
o <10 % remaining = effectively cleared from the body

Question 23

Repeated dosing

Answer 23

More practical
-o fluctuations in plasma concentrations
o aim: to keep plasma conc at/ above steady state level

Question 24

How can we quantify drug elimination?

Answer 24

Clearance = volume of plasma cleared of drug per unit time

Cl total = CL renal + Cl liver + Cl other

Question 25

Clearance is dependent on:

Answer 25

• Liver: hepatic blood flow, intrinsic clearance, concentration of drug in plasma
• Renal: conc of drug in urine, urine flow rate, conc of drug in plasma

Question 26

plasma half life

Answer 26

Time to eliminate drug is about 4-5 half lives

Time to reach steady state is 4-5 half lives (dosing frequency)

Question 27

First order drug elimination kinetics

Answer 27

Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration

Question 28

Zero order drug elimination kinetics

Answer 28

The plasma concentration – time profile during the elimination phase is linear. For example 1.2 mg are eliminated every hour, independently of the drug concentration in the body. Order 0 elimination is rather rare, mostly occurring when the elimination system is saturated.
No defined half life

Question 29

Rate of elimination, maintenance dose rate and the loading dose

Answer 29

RE = CL * [Plasma]
DR = CL * target []
LD = Vd * target [plasma]

Question 30

Phase 2 enzymes examples

Answer 30

• glutathione transferase

- N-acetyl transferase

Question 31

Pharmacogenetics of warfarin

Answer 31

• Metabolism occurs through CYP2C9
• Clinically relevant SNPs have been identified in CYP2C9
  o Result in reduced enzymatic activity
  o Decrease in metabolism
• Even after adjusting the dose for variability in CYP2C9 status, there is still an amount of dosing variability in patients with similar alleles
• Additional variability: polymorphisms in the warfarin target vitamin K reductase complex (VKORC1)

Question 32

polymorphisms in drug targets (pharmacodynamics)

Answer 32

• Receptors/ transporters/ ion channels/ growth factors are increasingly recognised as causing variation in drug response
• Polymorphisms can have direct effects on drug target genes that affect drug response

Question 33

polymorphisms in the β2 adrenoceptor

Answer 33

• Short acting β2-adrenoceptor stimulants (salbutamol) are used in the treatment of asthma (relaxing airways smooth muscle)
• Regular use of salbutamol had detrimental effects in the long term treatment of asthma
  o

1/6 of asthmatic patients have an arg/arg phenotype (codon 16) in the adrenoreceptor.
o This phenotype is associated with a strong response to an acute dose of salbutamol compared to the gly/gly phenotype

BUT

o With long term treatment, patients with arg/arg phenotype rapidly desensitise to beta agonist drugs, resulting in a decline in responsiveness
o Patients with the arg/arg phenotype should avoid long term use of beta 2 agonist bronchodilators.