Erblichkeit in der Aktivität der Enzyme CYP2D6 und CYP2C9 sowie des Transporters OATP1B1 unter Berücksichtigung der bereits bekannten genetischen Varianten

Abstract

BACKGROUND AND OBJECTIVES: It is well accepted that variability in drug responses can be explained by multiple environmental and genetic factors. The individual drug response to the same dose can range from therapy failure to toxic overdose and is strongly influenced by drug metabolizing enzymes and transporters. The interindividual differences concerning the activity of these enzymes and transporters are partially explained by genetic variants. However, it remains unknown which proportion of the variation in the activity can be ascribed to heritability but cannot be explained by known genetic variants. Primary aim of this study was to quantify the currently unexplained heritable fraction in the variation of the activity of the enzymes CYP2D6 and CYP2C9 as well as the transporter OATP1B1. METHODS: We studied heritability in the variation of the activity of CYP2D6, CYP2C9 and OATP1B1 in 20 monozygotic and 9 same sex dizygotic twin pairs. The probe drugs metoprolol (CYP2D6) and torsemide (CYP2C9 and OATP1B1) were repeatedly administered to each subject. The area under the curve to infinity (AUC0-inf) of each drug and its metabolite were defined as markers of enzyme (CYP2D6, CYP2C9) and transporter (OATP1B1) activity. Different approaches were applied to calculate heritability: Formulas using the correlation coefficients of the siblings of the mono- and dizygotic twin pairs; structural equation modeling, by dividing variation into genetic and environmental effects; repeated drug application methodology to assess intra- and interindividual differences. RESULTS: High heritability was calculated in the variation of the activity of CYP2D6, CYP2C9 and OATP1B1. Heritability was quantified between 88.5% - 100% for CYP2D6 and between 81% - 100% for CYP2C9 and OATP1B1. Known genetic variants only explained a small amount of the variation of AUC0-inf within our study population (38.2% could be explained by genetic variants in CYP2D6, 6.5% by genetic variants in CYP2C9 and 20.4% by genetic variants in OATP1B1). CONCLUSIONS: The analyses show that heritability has a great influence on the variation of activity of the enzymes CYP2D6, CYP2C9 and the transporter OATP1B1. However, known genetic variants only explain a small proportion of the measured heritability. Further research on genetic regulation of drug response seems to be promising.