Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions

• Published in: Clinical pharmacology and therapeutics Vol. 104; no. 1; p. 148
• Main Authors: Storelli, Flavia, Matthey, Alain, Lenglet, Sébastien, Thomas, Aurélien, Desmeules, Jules, Daali, Youssef
• Format: Journal Article
• Language: English
• Published: United States 01.07.2018
• Subjects: Adolescent; Adult; Alleles; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacokinetics; Antitussive Agents - metabolism; Antitussive Agents - pharmacokinetics; Cytochrome P-450 CYP2D6 - drug effects; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP2D6 Inhibitors - pharmacology; Dextromethorphan - metabolism; Dextromethorphan - pharmacokinetics; Drug Interactions; Duloxetine Hydrochloride - pharmacology; Female; Genotype; Heterozygote; Homozygote; Humans; Male; Paroxetine - pharmacology; Pharmacogenomic Variants; Phenotype; Tramadol - metabolism; Tramadol - pharmacokinetics; Young Adult
• ISSN: 1532-6535
• DOI: 10.1002/cpt.889

We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.