cyp2c8 and drug interactions pertti j. neuvonen, md department of clinical pharmacology university...
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CYP2C8 and Drug InteractionsCYP2C8 and Drug Interactions
Pertti J. Neuvonen, MD Department of Clinical Pharmacology
University of Helsinki & Helsinki University Central HospitalHelsinki, Finland
FDA Advisory Committee for Pharmaceutical SciencesClinical Pharmacology Subcommittee meeting,
November 18. 2003, Rockville, MD
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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
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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)
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Substrates of CYP2C8Substrates 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
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Amodiaquine metabolism and paclitaxel 6-alphahydroxylase activity
10 human livers
(Li et al., JPET 2002)
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Inhibitors of CYP2C8: trimethoprim
Inhibitors of CYP2C8: trimethoprim
• Trimethoprim
– competitive inhibitor of CYP2C8 (Ki 32 µM), relatively selective up to 100 µM
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Inhibition of CYPs by trimethoprim
CYP2C8
(Ki 32 µM)
(Wen et al., DMD 2002)
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Inhibition of CYPs by trimethoprim
(Wen et al., DMD 2002)
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Inhibitors of CYP2C8Inhibitors 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
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Ki values for glitazones Ki values for glitazones
CYP2C8 CYP2C9 CYP3A4
Rosiglitazone 5.59 29.9 36.3
Pioglitazone 1.69 32.1 11.8
Troglitazone 2.59 0.63 1.6
(Sahi et al., DMD 2003)
(Ki values, microM)
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Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes
(Ong et al., BrJCp 2000)
Ketoconazole also CYP2C8 inhibitor
Diethyldithiocarbamatealso CYP2C8 inhibitor
CYP2E1
CYP3A
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Induction of CYP2C8Induction 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)
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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
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(Backman et al. CPT 2002)
Effect of gemfibrozil on cerivastatin PKEffect of gemfibrozil on cerivastatin PK
AUC x 5-6
Cerivastatin (acid) Cerivastatin lactone
M-1 metabolite CYP3A4 M-23 metabolite CYP2C8
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(Wang et al. DMD 2002)
Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro
Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro
Ra
te o
f met
ab
olite
form
atio
n
M23; CYP2C8
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Gemfibrozil increases the AUC of simvastatin acid but NOT of the parent simvastatin
Gemfibrozil increases the AUC of simvastatin acid but NOT of the parent simvastatin
(Backman et al. CPT 2000)
Gemfibrozil: Simvastatin acid: AUC x 2.3
Simvastatin AUC: ~
Placebo
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CYP-enzymes in simvastatin metabolismCYP-enzymes in simvastatin metabolism
Simvastatin (0)
corresponding (active) acids
Carboxyl-esterase
CYP3A4
CYP3A4, CYP2C8Simvastatin acid
(100)
(Gruer et al., Am J Cardiol 1999; Prueksaritanont et al. BrJCP 2003)
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0 2 4 6 8 10 12 24
Time (h)
0
2
4
6
8
Lo
vast
atin
aci
d (
ng
/mL
)
B
0 5 10 15 20 25
Time (h)
0,0
0,5
1,0
1,5
2,0
2,5
Lova
stat
in (n
g/m
L)
A
Gemfibrozil unlike bezafibrate increases the AUC of lovastatin acid but NOT of the parent lovastatin
Gemfibrozil unlike bezafibrate increases the AUC of lovastatin acid but NOT of the parent lovastatin
(Kyrklund et al,. CPT 2001)
Gemfibrozil 600 mg x 2
Placebo
Bezafibrate 400 mg x 1
Lovastatin acid AUC: x 2.8
Lovastatin AUC: ~
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Gem 600mg x 2
Gem+itra
Itra 200mg x 1
M1-metabolite; CYP3A4Repaglinide
Effect of gemfibrozil, itraconazole and their combination on plasma repaglinide and its
M1-metabolite
(Niemi et al., Diabetologia 2003)
Gem 600mg x 2
Gem+itra
Placebo
nPlacebo Itra
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Effect of CYP3A4 inhibitors and gemfibrozil on the AUC of repaglinideEffect of CYP3A4 inhibitors and gemfibrozil on the AUC of repaglinide
(Niemi et al. CPT 2001, Diabetologia 2003)
Repaglinide AUC
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Effect of Gemfibrozil on Rosiglitazone
Gemfibrozil
Placebo
(Niemi et al., Diabetologia 2003)
Rosiglitazone AUC x 2.3
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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
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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