1. CYP2C8 and Drug Interactions
FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee meeting, November , Rockville, MD
CYP2C8 and Drug Interactions
Pertti J. Neuvonen, MD Department of Clinical Pharmacology University of Helsinki & Helsinki University Central Hospital Helsinki, Finland

2. Outline Expression and Substrates of CYP2C8 Inhibitors of CYP2C8
Inducers of CYP2C8
In vivo interaction studies with CYP2C8 substrates
Suggestions for in vitro and in vivo studies

3. CYP2C8 expression CYP2C8 is
highly expressed in the liver (CYP2C protein content: CYP2C9 >~ CYP2C8 > CYP2C19)
large interindividual variation
not detectable in the intestine
(Läpple et al., Pharmacogenetics 2003)

4. Substrates of CYP2C8 Paclitaxel (taxol); (-> 6-alpha-OH-paclitaxel)
Amodiaquine (-> N-desethyl-amodiaquine)
Torsemide (-> tolyl-methyl-OH-T; CYP2C9 > CYP2C8)
Cerivastatin (CYP2C8 > CYP3A4)
Repaglinide (CYP2C8 > CYP3A4)
Rosiglitazone (CYP2C8 > CYP2C9)
Several other drugs; Contribution of different CYPs may depend on substrate concentration

5. Amodiaquine metabolism and paclitaxel 6-alphahydroxylase activity
10 human livers
(Li et al., JPET 2002)

6. Inhibitors of CYP2C8: trimethoprim
competitive inhibitor of CYP2C8 (Ki 32 µM), relatively selective up to 100 µM

7. Inhibition of CYPs by trimethoprim
CYP2C8
(Ki 32 µM)
(Wen et al., DMD 2002)

8. Inhibition of CYPs by trimethoprim
(Wen et al., DMD 2002)

9. Inhibitors of CYP2C8 Trimethoprim Quercetin
competitive inhibitor of CYP2C8 (Ki 2 µM), inhibits also CYP1A2
”Glitazones” (thiazolidinediones)
Gemfibrozil; nonselective; in vitro and in vivo
Other nonselective inhibitors

10. Ki values for glitazones
CYP2C8 CYP2C9 CYP3A4
Rosiglitazone
Pioglitazone
Troglitazone
(Sahi et al., DMD 2003)
(Ki values, microM)

11. Diethyldithiocarbamate
Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes
Diethyldithiocarbamate
also CYP2C8 inhibitor
CYP2E1
Ketoconazole also
CYP2C8 inhibitor
CYP3A
(Ong et al., BrJCp 2000)

12. Induction of CYP2C8 In vitro: CYP2C8 is inducible
Rifampin: CYP2C8 >CYP2C19, CYP2C9
Rifampin>Phenobarb.>Dexamethasone
(Raucy et al., JPET 2002)
In vivo: Rifampin decreases the AUC of repaglinide by about 60% (30-78%)
(Niemi et al., CPT 2000)

13. In vivo studies: Gemfibrozil + Statins / Oral Antidiabetics
Randomized, cross-over, healthy volunteers
Gemfibrozil 1200 mg/d or placebo/comparator for 3-4 days
On day 3, a single dose of
Cerivastatin
Simvastatin
Lovastatin (Gemfibrozil, Bezafibrate, Placebo)
Repaglinide (Gemfibr., Itraconazol, Gem+Itra, Plac)
Rosiglitazone

14. Effect of gemfibrozil on cerivastatin PK
Cerivastatin (acid)
Cerivastatin lactone
AUC x 5-6
M-23 metabolite CYP2C8
M-1 metabolite CYP3A4
(Backman et al. CPT 2002)

15. Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro
Rate of metabolite formation
M23; CYP2C8
(Wang et al. DMD 2002)

16. Gemfibrozil increases the AUC of simvastatin acid but NOT of the parent simvastatin
Gemfibrozil: Simvastatin acid: AUC x 2.3
Simvastatin AUC: ~
Placebo
(Backman et al. CPT 2000)

17. CYP-enzymes in simvastatin metabolism
Carboxyl-esterase
Simvastatin (0)
CYP3A4
Simvastatin acid
(100)
CYP3A4, CYP2C8
corresponding (active) acids
(Gruer et al., Am J Cardiol 1999; Prueksaritanont et al. BrJCP 2003)

18. Gemfibrozil unlike bezafibrate increases the AUC of lovastatin acid but NOT of the parent lovastatin
Lovastatin AUC: ~
Gemfibrozil 600 mg x 2
Lovastatin acid AUC: x 2.8
Bezafibrate 400 mg x 1
Placebo
(Kyrklund et al,. CPT 2001)

19. (Niemi et al., Diabetologia 2003)
Effect of gemfibrozil, itraconazole and their combination on plasma repaglinide and its M1-metabolite
Gem 600mg x 2
Gem+itra
Itra 200mg x 1
M1-metabolite; CYP3A4
Repaglinide
Gem 600mg x 2
Placebo
Gem+itra
Placebo
Itra n
(Niemi et al., Diabetologia 2003)

20. Effect of CYP3A4 inhibitors and gemfibrozil on the AUC of repaglinide
Repaglinide AUC
(Niemi et al. CPT 2001, Diabetologia 2003)

21. Effect of Gemfibrozil on Rosiglitazone
Rosiglitazone AUC x 2.3
Gemfibrozil
Placebo
(Niemi et al., Diabetologia 2003)

22. CYP2C8: in vitro interaction studies
Human liver microsomes, or recombinant human CYP2C8 isoform
Substrates:
paclitaxel, amodiaquine
torsemide (only with recombinant CYP2C8)
Inhibitors:
trimethoprim, quercetin, pio/rosiglitazone
Inducers:
rifampin

23. CYP2C8: in vivo interaction studies
Probe substrates:
repaglinide (obs. hypoglycemia)
rosiglitazone
cerivastatin? (availability?); amodiaquine?? (toxic)
Inhibitors:
gemfibrozil (nonselective, e.g. CYP2C9 and OATP2)
trimethoprim (in vivo data as inhibitor?)
pio/rosiglitazone (in vivo data as inhibitors?)
Inducers: rifampin (nonselective)
Further studies are needed to find optimal probe substrates and inhibitors, particularly for in vivo interaction studies