1. Clarifications of Lecture #36- Drug Interactions I

2. Mutual Effects

3. Mutual Effects * Drug Displaced Unbound Bound 100% Drug * 0% C D C D C
Low Extraction Ratio
IV or Oral
High Extraction Ratio IV
High Extraction Ratio
Oral
100%
Drug * 0% C D C D C D
Clearance
[Drug]plasma

4. Mutual Effects * Drug Displaced Unbound Bound [Drug] * C D C D C D
Low Extraction Ratio
IV or Oral
High Extraction Ratio IV
High Extraction Ratio
Oral
[Drug] * C D C D C D
* Unbound [Drug] the same for Low Extraction Ratio and High Extraction Ratio Oral.

5. Mutual Effects
D = Displaced
C = Control
Total
Unbound

6. Mutual Effects anti-seizure anti-seizure Extraction Ratio?
* This is consistent with increased clearance following displacement from the plasma protein binding site of a highly bound drug with a low hepatic extraction ratio [34].
anti-seizure
Extraction Ratio?

7. Aside: Question of Effect of Ethanol and Benzodiazepines on an Action Potential

8. Action Potential

9. Action Potential
Depolarization
Repolarization

10. Channel Types Chloride Channels Potassium Channels Sodium Channels
Voltage-gated
Resting Potential (-70 mV)
Ligand-gated Chloride Channels
GABAA Receptor
Potassium Channels
Sodium Channels
Voltage-gated/Ligand-gated

13. Effect of Ethanol or Benzodiazepines
Threshold
Hyperpolarization
Hyperpolarization
effect of ethanol/benzodiazepines
More difficult to initiate action potentials. 15 mV difference  45 mM difference.

14. Lecture #37
Drug Interactions II

15. Interaction Types Mutual Effects Bidirectional Effects
Competing for the same target
Bidirectional Effects
Unidirectional Effects
AB
Beneficial Interactions

16. Beneficial Drug Combinations: Inhibit Metabolism
penicillin antibiotic
dehydropeptidase
inhibitor
renal
dehydropeptidase
Metabolites

17. Beneficial Interactions

18. Condition
PK Effects
Metabolism inhibited
Increased t1/2, Decreased CL
Metabolism Induced
Decreased t1/2, Increased CL

19. Condition
PK Effects
CL reduced
C avg, ss, altered increased
CL increased
C avg, ss, altered decreased

21. Effect of Inhibitors
fm = fraction down the metabolism route; CuI = concentration unbound inhibitor.

22. Effect of Inhibitors

24. NF-AT = nuclear factor activated T cell
Cholesterol Lowering
immunosuppressant
NF-AT = nuclear factor activated T cell
transcription factor

25. Effect of Inhibitors Cholesterol Lowering CYP2C9 substrate
immunosuppressant
CYP2C9 inhibitor

26. Route of Administration
CYP3A
inhibitor
Cholesterol Lowering Drug
Calcium Channel Blocking Drug

28. Route of Administration
anti-fungal
CYP3A inhibitor
sedative

29. Mechanism-Based Inhibition

30. kobs = rate constant kinact observed kinact = rate of inactivation
KI = inhibitory constant
Y = [I]/(KI+[I])
Remove Slide

31. Mechanism-Based Inhibition

32. Mechanism-Based Inhibition
+ Clarithromycin
+ Clarithromycin
Antibiotic
Sedative

33. Induction anticoagulant anti-seizure/CYP 2C9 inducer
anticoagulant
anti-seizure/CYP 2C9 inducer

34. Multi-faceted Interactions
Examples
Displace protein binding and inhibit metabolism
Compete with PD target and inhibit metabolism
Displace protein binding and induce metabolism

35. Multi-faceted Interactions
anti-coagulant
Inhibition
of Elimination
Phenylbutazone is AKA bute
Phenylbutazone displaces Warfarin from Albumin
The spike suggests that CYP
NSAID
Phenylbutazone
Protein Binding Displacement
Inhibit Elimination

36. Multi-faceted Interactions
Na+/K+ ATPase Inhibitor
Quinidine
Displaces from tissues (Decreases V)
Inhibits Pgp
Na+/K+ ATPase Inhibitor

37. P-gp Inhibition Cause Effect increase intestinal absorption
decrease biliary clearance
decrease renal clearance
Effect
decreased biliary and renal clearance
increased absorption rate (ka)
increased AUC

38. Multi-faceted Interactions
Rifampicin is a CYP3A inducer.
Rifampicin is a uptake transport inhibitor (OATP1B1 inhibitor)
antibiotic
CYP3A inducer/OATP1B1 inhibitor
cholesterol lowering (Lipitor)

39. PD: Additive Effects
Saturating A
No A

40. Isobologram
Isobologram- Equal concentrations across both axes;
or IC50
Line on an Isobologram (Black, Red, Gray) = Isobole

41. mTOR = mammalian target of rapamycin
a.k.a. rapamycin
Cotylenin A
mTOR = mammalian target of rapamycin
gbL = positive regulator of rapamycin-sensitive pathway
Raptor (RPTOR)= Regulator-associated protein of mTOR
Bcl-2 = B-cell lymphoma 2 (inhibited)
induce promote apoptosis
reduce apoptosis (rapamycin)
BAD (inhibited)
p53 (activated)
Inhibits G1-S cell cycle progression

42. Isobologram Cotylenin A Rapamycin = Sirolimus
Rapamycin = Sirolimus