# Presentation: 187998

## CYP2C8 and Drug Interactions

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

*FDA Advisory Committee for Pharmaceutical Sciences**Clinical 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 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 

- 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**
**	****	****	****	****	****	**(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**

**Diethyldithiocarbamate**
**also CYP2C8 inhibitor**

**CYP2E1**

**CYP3A**

## 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

*(Backman et al. CPT 2002)*

**AUC x 5-6**

- Cerivastatin (acid)

- Cerivastatin lactone

- M-1 metabolite CYP3A4

- M-23 metabolite CYP2C8** **

## Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) in vitro

- Gemfibrozil inhibits cerivastatin metabolism (CYP2C8) *in vitro*

- Rate of metabolite formation

**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 metabolism

**Simvastatin**** (0)**

**Carboxyl-esterase**

**CYP3A4**

**CYP3A4, CYP2C8**

**Simvastatin acid**
** ****(100)**

- (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

- 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:  ****~**** **

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

**M1-metabolite; **CYP3A4

**Repaglinide**

- 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

**n**

- Placebo

- Itra

## Effect 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