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

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

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)

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

Amodiaquine metabolism and paclitaxel 6-alphahydroxylase activity

10 human livers

(Li et al., JPET 2002)

Inhibitors of CYP2C8: trimethoprim

Inhibitors of CYP2C8: trimethoprim

• Trimethoprim

– competitive inhibitor of CYP2C8 (Ki 32 µM), relatively selective up to 100 µM

Inhibition of CYPs by trimethoprim

CYP2C8

(Ki 32 µM)

(Wen et al., DMD 2002)

Inhibition of CYPs by trimethoprim

(Wen et al., DMD 2002)

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

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)

Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes

(Ong et al., BrJCp 2000)

Ketoconazole also CYP2C8 inhibitor

Diethyldithiocarbamatealso CYP2C8 inhibitor

CYP2E1

CYP3A

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)

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

(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

(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

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

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)

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: ~

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

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

Effect of Gemfibrozil on Rosiglitazone

Gemfibrozil

Placebo

(Niemi et al., Diabetologia 2003)

Rosiglitazone AUC x 2.3

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

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