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					 FDA Advisory Committee for Pharmaceutical Sciences
    Clinical 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 Hospital
                      Helsinki, Finland
              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 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

• 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 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

                CYP2C8 CYP2C9 CYP3A4
Rosiglitazone 5.59           29.9           36.3
Pioglitazone          1.69   32.1           11.8
Troglitazone          2.59   0.63            1.6
(Ki values, microM)
                                    (Sahi et al., DMD 2003)
         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

• 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
Effect of gemfibrozil on cerivastatin PK
        Cerivastatin (acid)          Cerivastatin lactone


              AUC x 5-6




       M-1 metabolite CYP3A4   M-23 metabolite CYP2C8




                                       (Backman et al. CPT 2002)
Gemfibrozil inhibits cerivastatin
metabolism (CYP2C8) in vitro
  Rate of metabolite formation




                                 M23; CYP2C8




                                               (Wang et al. DMD 2002)
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)
CYP-enzymes in simvastatin metabolism
                            Carboxyl-
                            esterase

 Simvastatin (0)
                   CYP3A4               Simvastatin acid
                                             (100)




                                                           corresponding
                                                           (active) acids




                                                   (Gruer et al., Am J Cardiol 1999;
                                                  Prueksaritanont et al. BrJCP 2003)
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)
Effect of gemfibrozil, itraconazole and their
combination on plasma repaglinide and its
              M1-metabolite
           Repaglinide                              M1-metabolite; CYP3A4

             Gem+itra

                                                                Gem 600mg x 2


             Gem 600mg x 2
                                                      Placebo

     Itra 200mg x 1
                                                                Gem+itra

 Placebo
    n                                              Itra



                        (Niemi et al., Diabetologia 2003)
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

          Rosiglitazone
           AUC x 2.3



              Gemfibrozil



        Placebo




                            (Niemi et al., Diabetologia 2003)
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

				
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