Cyp2c8 and drug interactions
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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

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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


Outline

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 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

CYP2C8

(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

CYP2C8 CYP2C9 CYP3A4

Rosiglitazone 5.5929.936.3

Pioglitazone 1.6932.111.8

Troglitazone 2.590.63 1.6

(Sahi et al., DMD 2003)

(Ki values, microM)


Cyp2c8 and drug interactions

Inhibition of CYP2C8 by prototypic CYP isoform ”selective” probes

Diethyldithiocarbamate

also CYP2C8 inhibitor

CYP2E1

Ketoconazole also

CYP2C8 inhibitor

CYP3A

(Ong et al., BrJCp 2000)


Induction of cyp2c8

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)


In vivo studies gemfibrozil statins oral antidiabetics

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


Cyp2c8 and drug interactions

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)


Cyp2c8 and drug interactions

Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro

Rate of metabolite formation

M23; CYP2C8

(Wang et al. DMD 2002)


Cyp2c8 and drug interactions

Gemfibrozilincreases 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)


Cyp2c8 and drug interactions

corresponding (active) acids

CYP-enzymes in simvastatin metabolism

Carboxyl-esterase

Simvastatin (0)

CYP3A4, CYP2C8

CYP3A4

Simvastatin acid

(100)

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


Cyp2c8 and drug interactions

Gemfibrozilunlike 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)


Cyp2c8 and drug interactions

Gem+itra

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

Repaglinide

Gem 600mg x 2

Placebo

Gem+itra

Placebo

Itra

n

(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

Rosiglitazone AUC x 2.3

Gemfibrozil

Placebo

(Niemi et al., Diabetologia 2003)


Cyp2c8 in vitro interaction studies

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

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


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