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FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee meeting, November 18. 2003, Rockville, MD. CYP2C8 and Drug Interactions.

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Cyp2c8 and drug interactions

FDA Advisory Committee for Pharmaceutical SciencesClinical Pharmacology Subcommittee meeting, November 18. 2003, Rockville, MD

CYP2C8 and Drug Interactions

Pertti J. Neuvonen, MD Department of Clinical Pharmacology University of Helsinki & Helsinki University Central HospitalHelsinki, Finland


  • 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 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 cyp2c8
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

Amodiaquine metabolism and paclitaxel 6 alpha hydroxylase activity
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
Inhibition of CYPs by trimethoprim


(Ki 32 µM)

(Wen et al., DMD 2002)

Cyp2c8 and drug interactions

Inhibition of CYPs by trimethoprim

(Wen et al., DMD 2002)

Inhibitors of cyp2c8
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

Cyp2c8 and drug interactions

Ki values for glitazones


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)

Cyp2c8 and drug interactions

Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes


also CYP2C8 inhibitor


Ketoconazole also

CYP2C8 inhibitor


(Ong et al., BrJCp 2000)

Induction of cyp2c8
Induction of CYP2C8 ”selective” probes

  • 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
In vivo ”selective” probes 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

Cyp2c8 and drug interactions

Effect of gemfibrozil on cerivastatin PK ”selective” probes

Cerivastatin (acid)

Cerivastatin lactone

AUC x 5-6

M-23 metabolite CYP2C8

M-1 metabolite CYP3A4

(Backman et al. CPT 2002)

Cyp2c8 and drug interactions

Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) ”selective” probesin vitro

Rate of metabolite formation

M23; CYP2C8

(Wang et al. DMD 2002)

Cyp2c8 and drug interactions

Gemfibrozil ”selective” probesincreases the AUC of simvastatin acid but NOT of the parent simvastatin

Gemfibrozil: Simvastatin acid: AUC x 2.3

Simvastatin AUC: ~


(Backman et al. CPT 2000)

Cyp2c8 and drug interactions

corresponding (active) acids ”selective” probes

CYP-enzymes in simvastatin metabolism


Simvastatin (0)



Simvastatin acid


(Gruer et al., Am J Cardiol 1999; Prueksaritanont et al. BrJCP 2003)

Cyp2c8 and drug interactions

Gemfibrozil ”selective” probesunlike 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


(Kyrklund et al,. CPT 2001)

Cyp2c8 and drug interactions

Gem+itra ”selective” probes

Gem 600mg x 2

Itra 200mg x 1

Effect of gemfibrozil, itraconazole and their combination on plasma repaglinide and its M1-metabolite

M1-metabolite; CYP3A4


Gem 600mg x 2






(Niemi et al., Diabetologia 2003)

Cyp2c8 and drug interactions

Effect of CYP3A4 inhibitors and gemfibrozil on the AUC of repaglinide

Repaglinide AUC

(Niemi et al. CPT 2001, Diabetologia 2003)

Effect of gemfibrozil on rosiglitazone
Effect of Gemfibrozil on Rosiglitazone repaglinide

Rosiglitazone AUC x 2.3



(Niemi et al., Diabetologia 2003)

Cyp2c8 in vitro interaction studies
CYP2C8: repaglinidein 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
CYP2C8: repaglinidein 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