Chronopharmacology

Question 1

What are the two things measured in chronopharmacology?

Answer 1

The effects of ‘the clock’ on drug action

The effect of drugs on ‘the clock’

Question 2

Describe the effect of circadian rhythms on pharmacokinetics (chronopharmacokinetics)

Answer 2

Known 24h rhythms in:

• gastric pH
• GI tract mobility
• Plasma binding proteins
• Liver/renal blood flow
• Liver metabolic activity
• Bile volume
• Renal glomerular filtration rate
• etc

Depending on drug ADME, there may be a ‘best time’ to take a drug

Question 3

What are two effects that time of drug delivery can have?

Answer 3

Effect on toxicity (5-FU)

• Can be due to rhythmic expression of metabolising enzyme

Effect on efficacy (Roscovitine)

Question 4

Describe the effect of circadian rhythms on target availability (chronopharmacodynamics)

Answer 4

If your target is clock-controlled or otherwise rhythmic, your drug’s efficacy will also be rhythmic

eg irinotecan (topoisomerase inhibitor)

rhythmic expression of Topo1 = rhythmic drug efficacy

eg BP and HR

Both decrease nocturnally, seeing a sharp rise when waking

Some hypertensives do not have this dip “non-dippers” (risk of CHF)

Question 5

How do we treat heart disease?

when are these most effective? How did we find this out?

Answer 5

With ARBs (angiotensin receptor blockers)

Most effective at bedtime (non-dippers don’t have this variation)

Hazard ratio (closer to 1 means no difference between states

Question 6

What are the classical drug targets?

What are possible targets for the circadian clock?

Answer 6

Classical drug targets: receptors, enzymes, ion channels

Possible targets:

• Kinases (CK1e/d)
• Phosphatases
• E3 Ligases
• Nuclear receptors (rev-erbalpha, RORs)
• Melatonin/vasopressin receptors

Question 7

What happens to the clock during a blockade of vasopressin receptors?

Answer 7

Vasopressin receptor blockade speeds re-entrainment following a large phase advance

Question 8

What was the effect of a CK1e/d inhibitor on FRP?

Answer 8

Longer FRP

Question 9

How can HTS be used to find modulators of circadian function?

Answer 9

Systems-based approach

• External signals
• CORE LOOP
• Metabolism, Physiology, Behaviour

Small molecule effects one of these things, measure alterations in period, amplitude, phase

Question 10

How do KL001 and longdaysin affect the circadian clock? How do they do this?

Answer 10

Both increase FRP

KL001/2 stabilizes CRY proteins by binding the FAD pocket (competes with E3 ligase FBXL3)

Longdaysin inhibits PER1 degradation