Drug-drug interactions and their harmful effects in hospitalised patients: a systematic review and meta-analysis

2018

Basic Clin Pharma Tox

Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O-demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non-functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of V in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters K , K and k was observed neither with the competitive inhibitor duloxetine nor with the time-dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype-sensitive magnitude of drug-drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles.

Section: Introductionmentioning

confidence: 99%

Genotype‐sensitive reversible and time‐dependent CYP2D6 inhibition in human liver microsomes

2018

Basic Clin Pharma Tox

“…To assess the reversible inhibition of CYP2D6 by duloxetine, various concentrations of duloxetine (0, 1, 2, 4, 8, 16, 32 and 64 μmol/L) were incubated with dextromethorphan at various concentrations (1,5,10,20 and 50 μmol/ L), HLMs (final protein concentration 0.5 mg/mL) and the NADPH generating system described above in phosphate buffer 0.1 mol/L pH 7.4 for 20 minutes. following 3-min.…”

Section: Reversible Inhibition By Duloxetinementioning

confidence: 99%

“…In a recent meta-analysis, the prevalence of potential unwanted DDIs was estimated to be 33% in general patients and 67% in intensive care patients during their hospital stay. 1 Cytochromes P450 (CYPs) constitute the main enzyme family responsible for oxidative drug metabolism and are highly relevant in the study of drug disposition due to their high variability in terms of expression and activity, which is mainly caused by genetic polymorphisms (especially for 2B6, 2C9, 2C19 and CYP2D6) and environmental factors such as DDIs. Despite its relatively poor abundance in the liver (<2%), CYP2D6 metabolizes a wide range of drugs, including opioid analgesics, antipsychotic, antidepressant and cardiovascular drugs.…”

Section: Introductionmentioning

confidence: 99%

Genotype-sensitive reversible and time-dependent CYP2D6 Inhibition in human liver microsomes

Drug Metabolism and Pharmacokinetics

2019

Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O-demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non-functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of V max in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters K i , K I and k inact was observed neither with the competitive inhibitor duloxetine nor with the time-dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype-sensitive magnitude of drug-drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles. K E Y W O R D SCYP2D6, drug-drug interaction, genetic polymorphisms, human liver microsomes, in vitro-in vivo extrapolation

“…Among them, CYP2D6 is of major clinical relevance as it metabolizes around 20% of marketed drugs and is characterized by a huge interindividual variability, which is mostly explained by genetic polymorphisms (>100 variant alleles have been described so far) . Despite the development of DDI prediction tools integrated in computerized physician order entry systems, it still remains difficult to predict the clinical relevance of potential DDIs, as shown by the significant discrepancy between the high prevalence of potential DDIs and the low prevalence of actual DDIs leading to clinical harm . Indeed, a large interindividual variability exists in the extent of CYP‐mediated DDIs, which might be explained by intrinsic factors, such as age, sex, comorbidities, and genetic polymorphisms .…”

mentioning

confidence: 99%

“…2 Despite the development of DDI prediction tools integrated in computerized physician order entry systems, it still remains difficult to predict the clinical relevance of potential DDIs, as shown by the significant discrepancy between the high prevalence of potential DDIs and the low prevalence of actual DDIs leading to clinical harm. 3 Indeed, a large interindividual variability exists in the extent of CYP-mediated DDIs, which might be explained by intrinsic factors, such as age, sex, comorbidities, and genetic 1 Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland; 2 Geneva-Lausanne School of Pharmacy, Geneva University, Geneva, Switzerland; 3 Faculty of Medicine, Geneva University, Geneva, Switzerland; 4…”

mentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Modeling for the Prediction of CYP2D6‐Mediated Gene–Drug–Drug Interactions

CPT Pharmacom & Syst Pharma

2019

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)‐mediated drug–drug interactions (DDIs) in different CYP2D6 genotypes using physiologically‐based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6‐mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan–duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio ( R pred/obs ) 1.38–1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan–paroxetine interaction, an R pred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene–drug–drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.