Impact of Genetic Polymorphism on Drug-Drug Interactions Involving CYP2D6

Risk of Phenoconversion in Genetic Extensive Metabolizers Healthy Volunteers Carriers of One Fully-Functional and One Non-Functional Allele Versus Carriers of Two Fully-Functional Alleles

CYP2D6 is characterized by a huge variability in the general population, mainly because of genetic polymorphism and drug-drug interactions (DDIs). CYP2D6 genotype is known to have an impact on the extent of DDIs. Indeed several studies have pointed out differential DDIs extent according to CYP2D6 genotype. The terms phenoconversion and phenotype switch are both used to describe the phenomenon by which a given subject changes his phenotype to another due external influence such as DDIs. When given a sufficiently strong CYP2D6 inhibitor, the phenotype of an individual with no mutant allele (extensive metabolizer, EM) of CYP2D6 can be modified to a poor metabolizer (PM) phenotype. This vulnerability is also thought to be dependent on CYP2D6 genotype. Various combinations of alleles predict an EM genotype, which represents about 60 to 70% of the general population. The aim of the study is to determine whether the presence of genetic mutation in CYP2D6 has an impact on DDIs involving the CYP2D6 enzyme. Our interest focuses on CYP2D6 EM carriers of two fully functional alleles and carriers of one non-functional and one functional allele. In order to elucidate this question, CYP2D6 activity will be measured on healthy volunteers by administration of single low doses of dextromethorphan and tramadol in presence or not of duloxetine and paroxetine, two known CYP2D6 inhibitors.

Inclusion Criteria:

• Healthy men and women
• Age 18-60 years
• Body Mass Index 18-27
• Understanding of French language and able to give a written inform consent
• CYP2D6 genotype : combination of two fully-functional (normal activity) alleles or of one fully-functional and one non-functional allele (null activity), according to table 1, without gene multiplication

Exclusion Criteria:

• Pregnant or breastfeeding woman
• Any pathologies, use of drugs or food that may affect CYP2D6 activity
• Regular smokers of >5 cigarettes/day
• Renal or hepatic impairment
• Medical history of chronic alcoholism or abuse of psychoactive drugs, including opiate addiction
• Liver transplantation
• Sensitivity to any of the drugs used
• Alteration of hepatic tests more than 2x normal
• Glomerular filtration rate < 60 ml/min/1.73m2