Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Haertter, Sebastian

doi:10.1515/dmdi-2013-0032

Cited by 17 publications

(9 citation statements)

References 84 publications

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“…Conflicting results are reported in the literature with respect to the inducibility of CYP2D6. Whereas CYP2D6 is generally thought not to be inducible (Ingelman-Sundberg, 2005;Teh and Bertilsson, 2012;Haertter, 2013), a recent publication shows that it can be induced in hepatocyte cultures in the absence of dexamethasone (Farooq et al, 2016). More work is needed to confirm the in vitro observations from these two studies and to explore the mechanisms for regulation of CYP2D6.…”

Section: Discussionmentioning

confidence: 99%

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

et al. 2017

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The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles.

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Section: Discussionmentioning

confidence: 99%

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

et al. 2017

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“… 52 CYP2D6 is inhibited by fluoxetine, 53 quinidine 54 and bupropion. 55 Unlike other isozymes, CYP2D6 has no verified inductors, 56 but isoenzyme activity increases in the gestation period. 57 However, there are controversial data about its weak induction by dexamethasone and rifampicin.…”

Section: Role Of Cyp Isoenzymes In Drug Metabolismmentioning

confidence: 99%

The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo

Sychev

Ashraf

Svistunov

et al. 2018

DDDT

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Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays.

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“…Of all the hepatic cytochromes, CYP2D6 is the most ‘efficient’; its expression is relatively minor in the liver but it metabolizes a large number of xenobiotics, 25–30% of which are medicines used in man . Of all the cytochromes implicated in the metabolism of medicines, CYP2D6 is indisputably the most polymorphic and the activity of the proteins derived from these allelic variants may be classed in four levels: slow, intermediary, rapid and ultrarapid . Contrary to other hepatic cytochromes, its expression does not depend on environmental agents and is not inducible either by tobacco or alcohol or by natural or artificial steroids.…”

Section: Risks Of Pharmacokinetic Interactions Between Cannabinoids Amentioning

confidence: 99%

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review

Bouquié

Deslandes

Mazaré

et al. 2018

Fundamemntal Clinical Pharma

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Cannabis is a plant that has been used for centuries to relieve a wide range of symptoms. Since the 1960s, interest in medical research into this plant has grown steadily. Already very popular for recreational use, a growing number of consumers not accustomed to using cannabis for psychoactive purposes have begun to use it as an alternative or complement to mainstream pharmaceutical medicines. The principal unsubstantiated or 'social' uses of cannabis are based mainly on data that is at best controversial, but usually not scientifically proven. The aim of this review was to identify the scientific basis and reasons that lead patients with cancer to consume cannabis, and also to identify whether there is a risk of interaction between cannabis and anticancer medicines through drug transporters (P-glycoprotein and other ATP-binding cassette superfamily members) Cytochromes P450 (3A, 1A, 2B, 2C, 2D families…) and glucuronyl transferases.

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Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Cited by 17 publications

References 84 publications

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

The cytochrome P450 isoenzyme and some new opportunities for the prediction of negative drug interaction in vivo

Cannabis and anticancer drugs: societal usage and expected pharmacological interactions – a review

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