CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System-Results From the ADRED Study.

Katja S Just,Harald Dormann,Ingo Graeff,Miriam Böhme,Michael Steffens,Mathias Freitag,Catharina Scholl,Julia C Stingl,Marlen Schurig,Thomas Seufferlein,Matthias Schwab

doi:10.3389/fphar.2021.624104

Abstract

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, n = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, n = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, n = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.

Highlights

Central nervous system (CNS) drugs are often substrates of the phase-I enzyme cytochrome P450 (CYP) 2D6
Patients that presented to the emergency department (ED) with dizziness had more comorbidities and took more drugs suspected for causing adverse drug reactions (ADRs) symptoms
This study shows, to the best of our knowledge, for the first time an association of dizziness, an ADR symptom related to CNS function, with CYP2D6 activity leading to ED admission

Summary

Introduction

Central nervous system (CNS) drugs are often substrates of the phase-I enzyme cytochrome P450 (CYP) 2D6. Due to pharmacogenetic polymorphisms in CYP2D6, drug clearances may individually vary, thereby affecting drug efficacy and safety (Stingl and Viviani, 2015). Pharmacogenetic variability does not fully explain individual differences in drug exposure (Matthaei et al, 2015). CYP2D6 is not inducible but can be inhibited by several factors, including drug–drug interactions and disease-related factors (Ingelman-Sundberg et al, 2007). This might lead to a different CYP2D6 phenotype compared to the genotype-predicted phenotype. This phenomenon is called phenoconversion or phenocopying (Klomp et al, 2020)

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