Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic drugs in hospitalised psychiatric patients: a retrospective study

Tamminga, Wim J.; Wemer, J.; Oosterhuis, B.; Boer, Anthonius de; Vranckx, Stan; Drenth, Ben F. H.; Zeeuw, Rokus A. de; Leij, Lou F. M. H. de; Jonkman, J. H. G.

doi:10.1007/s00228-003-0562-x

Cited by 33 publications

(12 citation statements)

References 29 publications

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“…However, a study estimated that 20 patients would have to be genotyped so that 1 patient would benefit from the treatment [31]. Another retrospective study (241 patients) showed that anti-parkinson drugs were given twice as frequently in PMs [32]. In Asians, haloperidol and clozapine doses were shown to be lower than those in Caucasians, and toxicity appeared at a lower dose [24].…”

Section: Clinical Impact Of Cyp450 Polymorphisms On Drug Therapymentioning

confidence: 99%

Applications of CYP450 Testing in the Clinical Setting

et al. 2013

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Interindividual variability in drug response is a major clinical problem. Polymedication and genetic polymorphisms modulating drug-metabolising enzyme activities (cytochromes P450, CYP) are identified sources of variability in drug responses. We present here the relevant data on the clinical impact of the major CYP polymorphisms (CYP2D6, CYP2C19 and CYP2C9) on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available. CYP2D6 is responsible for the oxidative metabolism of up to 25 % of commonly prescribed drugs such as antidepressants, antipsychotics, opioids, antiarrythmics and tamoxifen. The ultrarapid metaboliser (UM) phenotype is recognised as a cause of therapeutic inefficacy of antidepressant, whereas an increased risk of toxicity has been reported in poor metabolisers (PMs) with several psychotropics (desipramine, venlafaxine, amitriptyline, haloperidol). CYP2D6 polymorphism influences the analgesic response to prodrug opioids (codeine, tramadol and oxycodone). In PMs for CYP2D6, reduced analgesic effects have been observed, whereas in UMs cases of life-threatening toxicity have been reported with tramadol and codeine. CYP2D6 PM phenotype has been associated with an increased risk of toxicity of metoprolol, timolol, carvedilol and propafenone. Although conflicting results have been reported regarding the association between CYP2D6 genotype and tamoxifen effects, CYP2D6 genotyping may be useful in selecting adjuvant hormonal therapy in postmenopausal women. CYP2C19 is responsible for metabolising clopidogrel, proton pump inhibitors (PPIs) and some antidepressants. Carriers of CYP2C19 variant alleles exhibit a reduced capacity to produce the active metabolite of clopidogrel, and are at increased risk of adverse cardiovascular events. For PPIs, it has been shown that the mean intragastric pH values and the Helicobacter pylori eradication rates were higher in carriers of CYP2C19 variant alleles. CYP2C19 is involved in the metabolism of several antidepressants. As a result of an increased risk of adverse effects in CYP2C19 PMs, dose reductions are recommended for some agents (imipramine, sertraline). CYP2C9 is responsible for metabolising vitamin K antagonists (VKAs), non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas, angiotensin II receptor antagonists and phenytoin. For VKAs, CYP2C9 polymorphism has been associated with lower doses, longer time to reach treatment stability and higher frequencies of supratherapeutic international normalised ratios (INRs). Prescribing algorithms are available in order to adapt dosing to genotype. Although the existing data are controversial, some studies have suggested an increased risk of NSAID-associated gastrointestinal bleeding in carriers of CYP2C9 variant alleles. A relationship between CYP2C9 polymorphisms and the pharmacokinetics of sulfonylureas and angiotensin II receptor antagonists has also been observed. The clinical impact in terms of hypoglycaemia and blood pressure was, however, modest. Finally, homoz...

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Section: Clinical Impact Of Cyp450 Polymorphisms On Drug Therapymentioning

confidence: 99%

Applications of CYP450 Testing in the Clinical Setting

et al. 2013

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“…48 Drugs against parkinsonian side effects were given twice more frequently in PMs among 241 psychiatric patients. 49 In a thorough study it was found that haloperidol clearance (n ¼ 172) correlated with the number of active CYP2D6 genes. Ratings for pseudoparkinsonism were higher in PMs and a trend towards lower therapeutic efficacy with increasing number of active CYP2D6 genes was seen.…”

mentioning

confidence: 99%

Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

2004

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CYP2D6 is of great importance for the metabolism of clinically used drugs and about 20-25% of those are metabolised by this enzyme. In addition, the enzyme utilises hydroxytryptamines as endogenous substrates. The polymorphism of the enzyme results in poor, intermediate, efficient or ultrarapid metabolisers (UMs) of CYP2D6 drugs. It is plausible that the UM genotype, where more than one active gene on one allele occurs, is the outcome of selective dietary selection in certain populations in North East Africa. The UM phenotype affects 5.5% of the population in Western Europe. A hypothesis for the evolutionary basis behind selection for CYP2D6 gene duplications is presented in relation to selection for Cyp6 variants in insecticide resistant Drosophila strains. The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The consequences of the polymorphism at ordinary drug doses can be either adverse drug reactions or no drug response. Examples are presented where CYP2D6 polymorphism affects the efficacy and costs of drug treatment. Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30-40% of CYP2D6 drug substrates, that is, for about 7-10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage based on the CYP2D6 genotype.

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“…Aut hors emp ha si zed that in di ca ti ons for a hig her in ci den ce of ADRs we re ob ser ved in PMs and phar macy re cords might be use ful to de tect dif feren ces re la ted to poly morp hic me ta bo lism. 28 Scordo et al de ter mi ned ge noty pes of a ran dom Ita li an po pu la ti on in or der to com pa re CYP2C9, CYP2C19 and CYP2D6 al le le fre qu en ci es. They fo und 3.4% PMs and 8.3% UMs for CYP2D6.…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 Polymorphism of Opiate Addicts and Contributions to Forensic Sciences

Açıkkol¹,

Mercan²

2011

Turkiye Klinikleri J Med Sci

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A AB BS S T TR RA AC CT T O Ob b j je ec c t ti i v ve e: : The CYP2D6 enz yme shows a wi de ran ge of poly morp hisms. It is respon sib le for the me ta bo lism of subs tan ces such as opi a tes that ha ve a gre at im por tan ce in fo rensic sci en ces. Ho we ver, so me mu ta ti ons da ma ge the ac ti vity of this enz yme and ca u se in ter rup ti on in me ta bo lism of the drugs which may le ad to unex pec ted ad ver se drug re ac ti ons, even to de ath. Alt ho ugh many stu di es ha ve de alt with CYP2D6 poly morp hism, the re is no re se arch con cer ning CYP2D6 enz yme poly morp hism and opi a te de pen den ce in our co untry. M Ma a t te e r ri i a al l a an nd d M Me et t h ho od ds s: : We ai med to in ves ti ga te the sing le nuc le o ti de poly morp hisms of CYP2D6*3, *4 and *6 al le les. Forty ni ne opi a te ad dicts and 34 con trol samp les we re stu di ed using tet ra-pri mer poly me ra se cha in re ac ti on (PCR) tech ni qu e in a sing le tu be and by dividing the pro to col in to two steps. R Re e s su ul lt ts s: : CYP2D6*4 and CYP2D6*6 al le les fre qu en ci es we re de ter mi ned as 0.082 and 0.031, res pec ti vely, however no sig ni fi cant re sult was ob ta i ned for CYP2D6*3. Al le le and ge noty pe fre qu en ci es of CYP2D6*4 and *6 for both opi a te ad dicts and con trol gro up we re in concordance with the Hardy-We in berg equ a ti on. C Co on nc c l lu u s si i o on n: : We sug gest that detection of CYP2D6 poly morp hism may cla rify the sud den-unex pec ted de aths du e to in to xi ca ti on of opi a te ad dicts and so me ne ga ti ve au topsy ca ses re la ted to me di cal or il licit drugs.K Ke ey y W Wo or rd ds s: : Pharmacogenetics; cytochrome P-450 CYP2D6; opioid-related disorders; drug toxicity Ö ÖZ ZE ET T A Am ma aç ç: : CYP2D6 en zi mi çok çe şit li po li mor fizm le ri gös te re bil mek te dir ve opi yat lar gi bi adli tıp bi li min de bü yük öne mi olan mad de le rin me ta bo liz ma sın dan so rum lu dur. Ay rı ca ba zı mutas yon lar bu en zi min ak ti vi te si ni bo zar ve alı nan ilaç la rın me ta bo liz ma sı nı ke sin ti ye uğ ra tır lar ki bu da bek len me yen ad vers ilaç re ak si yon la rı na hat ta ölü me yol aça bi lir. CYP2D6 po li mor fiz mi ile il gi li bir çok ça lış ma ol sa da bi zim ül ke miz de CYP2D6 en zim po li mor fiz mi ve opi yat ba ğım lı lı ğı ile il gi li ça lış ma bu lun ma mak ta dır. G Ge e r re eç ç v ve e Y Yö ön n t te em m l le er r: : CYP2D6*3, *4 ve *6 al lel le rin de ki tek nük le o tid po li mor fizm le ri ni araş tır ma yı amaç la dık. 49 opi yat ba ğım lı sı ve 34 kon trol den alı nan ör nek tet ra-pri mer po li me raz zin cir re ak si yo nu (PCR) tek ni ği ile tek tüp te ve pro to ko lü iki aşa-ma ya bö le rek ça lı şıl dı. B Bu ul l g gu u l la ar r: : CYP2D6*4 ve CYP2D6*6 al lel sık lık la rı sı ra sıy la 0.082 ve 0.031 ola rak be lir len di, bu nun la bir lik te CYP2D6*3 al le li ile il gi li hiç bir an lam lı so nuç el de edi le me di. Hem opi yat ba ğım lı la rı hem de kon trol gru bu için CYP2D6*4 ve *6'nın al lel ve ge no tip sık ...

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Polymorphic drug metabolism (CYP2D6) and utilisation of psychotropic drugs in hospitalised psychiatric patients: a retrospective study

Cited by 33 publications

References 29 publications

Applications of CYP450 Testing in the Clinical Setting

Applications of CYP450 Testing in the Clinical Setting

Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

CYP2D6 Polymorphism of Opiate Addicts and Contributions to Forensic Sciences

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