Browsing by Subject "CYP2D6"

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  • Wendt, Frank R.; Novroski, Nicole M. M.; Rahikainen, Anna-Liina; Sajantila, Antti; Budowle, Bruce (2019)
    Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.
  • Goncalves, Bronner P.; Pett, Helmi; Tiono, Alfred B.; Murry, Daryl; Sirima, Sodiomon B.; Niemi, Mikko; Bousema, Teun; Drakeley, Chris; ter Heine, Rob (2017)
    Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine.
  • Cajanus, Kristiina; Neuvonen, Mikko; Koskela, Outi; Kaunisto, Mari A.; Neuvonen, Pertti J.; Niemi, Mikko; Kalso, Eija (2018)
    We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/mL (66%) and it was 21.7 ng/mL (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals. The analgesic oxycodone concentration was increased by 21.3% per motion pain intensity score on a 0-10 scale and by 22.3% if axillary clearance was performed instead of sentinel node biopsy (P <0.001). Forty-seven women who were older and less anxious than others (P <0.01) required no oxycodone. Anxiety, age, chronic pain, or preoperative pain sensitivity were not independently associated with the analgesic oxycodone concentration. CYP2D6 and CYP3A genotypes did not affect analgesic concentration or duration of analgesia.
  • Koskela, Outi (Helsingfors universitet, 2012)
    Pharmacogenetics is the study of variations in DNA sequence as related to drug response, i.e. pharmacokinetics, drug efficacy and adverse effects. The literature review of the thesis covers pharmacogenetics of analgesics. The most studied genetic variations affecting the analgesics response are the 118A>G variant of µ-opioid receptor gene (OPRM1) and several variations in the genes coding for cytochrome (CYP) P450 enzymes. Also variations in the COMT gene and the ABCB1 gene coding for P-glycoprotein have been shown to modify the response to analgesics. Genetic polymorphism of CYP2D6, CYP3A4 and CYP3A5 enzymes was studied in the experimental part of the thesis. The aim of the study was to determine if the allele and haplotype frequencies of the CYP2D6, CYP3A4 and CYP3A5 gene variations are different between Finnish breast cancer patients and healthy volunteers. The results will be further used to explore whether the genetic polymorphism of these metabolic enzymes affects the response to a certain drug substance. The study population consisted of 996 Finnish breast cancer patients. Common genetic variants affecting the enzymatic activity of CYP2D6, CYP3A4 and CYP3A5 were studied. In addition to gene copy number, ten single nucleotide polymorphisms (SNP) of the CYP2D6 gene were genotyped. For CYP3A4 gene, genotyping was done for intron 6 SNP rs35599367 shown to decrease CYP3A4 gene expression. CYP3A5 SNP 6986A>G leading to splicing defect and premature STOP codon was also genotyped. Genotyping and copy number determination was done using PCR-based TaqMan® 5'-nuclease method. CYP2D6 haplotype analysis and phenotype predictions were derived based on genotype data. According to CYP2D6 enzyme activity individuals are commonly classified as poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) or ultra-rapid metabolizers (UM). The frequencies of CYP2D6 phenotypic classes in our study population were the following: PM, 2.8%; IM 2.0 %; EM 87.7% and UM 7.6%. The haplotype and phenotype frequencies determined for breast cancer patients coincide with the values observed earlier for Finnish healthy volunteers. In our study population, the minor allele frequency (MAF) of the CYP3A4 rs35599367 SNP was 2.7% and the MAF of the CYP3A5 6986G>A SNP 7.6%. The MAF of CYP3A5 6986G>A SNP found in our study is in line with the previous findings for Finnish healthy volunteers. There are no previous publications on the frequency of CYP3A4 rs35599367 SNP in Finnish population. In conclusion, no differences were detected in the frequency of the studied CYP2D6 and CYP3A5 genetic variations between Finnish breast cancer patients and healthy volunteers. Frequency of CYP3A4 rs35599367 SNP in Finnish healthy volunteers should be determined in order to compare it with our findings in the population comprising of breast cancer patients. The results of this study can be further used to explore the effects of CYP2D6, CYP3A4 and CYP3A5 genetic polymorphism on drug response.
  • Wendt, Frank R.; Sajantila, Antti; Moura-Neto, Rodrigo S.; Woerner, August E.; Budowle, Bruce (2018)
    CYP2D6 is a critical pharmacogenetic target, and polymorphisms in the gene region are commonly used to infer enzyme activity score and predict resulting metabolizer phenotype: poor, intermediate, extensive/normal, or ultrarapid which can be useful in determining cause and/or manner of death in some autopsies. Current genotyping approaches are incapable of identifying novel and/or rare variants, so CYP2D6 star allele definitions are limited to polymorphisms known a priori. While useful for most predictions, recent studies using massively parallel sequencing data have identified additional polymorphisms in CYP2D6 that are predicted to alter enzyme function but are not considered in current star allele nomenclature. The 1000 Genomes Project data were used to produce full-gene haplotypes, describe their distribution in super-populations, and predict enzyme activity scores. Full-gene haplotypes generated lower activity scores than current approaches due to inclusion of additional damaging polymorphisms in the star allele. These findings are critical for clinical implementation of metabolizer phenotype prediction because a fraction of the population may be incorrectly considered normal metabolizers but actually may be poor or intermediate metabolizers.
  • Pietarinen, Paavo (Helsingfors universitet, 2012)
    Most xenobiotics are biotransformed by phase I enzymes to a more hydrophilic form in order to get excreted out from the body. In most cases xenobiotics are in lipophilic form when entering body. The most important group in phase I enzymes is cytochrome P450 (CYP) superfamily. Of CYP enzymes probably the most studied is CYP2D6, which is responsible for metabolism of 20-25% of drugs currently on market. Many CYP2D6 substrates belong to therapeutically important drug groups, such as antiarrhytmics, antidepressants, beta-blockers, or neuroleptics. CYP2D6 gene, which encodes the enzyme, exhibits large interindividual variability, which has an effect on the metabolic activity of the enzyme. The frequencies of these genetic variances differ globally on wide scale between and inside populations. Through genotyping it is possible to predict the CYP2D6 metabolic rate, which can be divided into four classes: ultra-rapid metabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). The purpose of our study was to examine the frequencies of CYP2D6 genotypes in Finnish population in detail and compare the results to previous studies. Our study population consisted of 857 healthy volunteers whose DNA was extracted. From DNA sample we genotyped 10 different CYP2D6 genetic variants and the copy number of the gene using Applied Biosystems TaqMan genotyping and copy number assays. This study was the largest CYP2D6 genotype frequency study in Finnish population so far. The results supported the findings of a similar study in a Finnish population of smaller scale. Large majority of study subjects were EMs (87.3%) and the second largest group was Ums (7.2%). IMs and PMs were in clear minority (3.0% and 2.5%, respectively). The expected frequencies for UMs (1-2%) are much lower and for PMs higher (~8%) in other North European populations than in Finns. Accordingly, CYP2D6 genetic profile of Finnish population differs from its neighbours, which may be important for the dose requirements, efficacy, and safety for drugs metabolized by CYP2D6.
  • Wendt, Frank R.; Sajantila, Antti; Budowle, Bruce (2018)
    The pharmacogene, CYP2D6, is commonly used to infer metabolizer phenotype of many marketed drugs and endogenous toxins in ante- and post-mortem patients but only represents the efficiency of phase 1 metabolism. Downstream metabolic enzymes encoded by UGT2B7, ABCB1, OPRM1, and COMT also have been implicated in variable individual response to drugs due to their activity at different stages of the tramadol ADME (absorption, distribution, metabolism, and excretion) process. While commonly studied as single genes using targeted genotyping approaches, a more comprehensive tramadol metabolism profile has not been evaluated. 1000 Genomes Project data for UGT2B7, ABCB1, OPRM1, and COMT were used to characterize full-gene haplotypes and their effect on protein function using in-house excel-based workbooks, PopART, and TreeView. Population genetic summary statistics and intergenic analyses associated these haplotypes with full-gene CYP2D6-inferred metabolizer phenotype. The findings suggest that UGT2B7, ABCB1, OPRM1, and COMT may contribute to predicted metabolizer phenotype as opposed to relying solely on CYP2D6.
  • Järvinen, Hanna (Helsingfors universitet, 2017)
    Interindividual variability in drug responses can complicate the determination of drug doses and increase drug-related risks. The variability can be caused by pharmacokinetics or pharmacodynamics of drug. One significant factor giving rise to the variability in the pharmacokinetics is the genetic polymorphism of cytochrome P450 (CYP) enzymes. CYP2C19 and CYP2D6 are highly polymorphic enzymes and many of their polymorphisms are well-known. For both genes there exist null alleles producing the enzyme with complete lack of function and alleles producing increased enzyme activity. Additionally there are alleles of CYP2D6 leading to partially deficient enzyme function. Based on the genotype of the CYP gene individuals can be divided into four phenotype groups describing the enzyme activity: poor, intermediate, extensive and ultrarapid metabolizers. According to the clinical observations the pharmacokinetics of CYP2C19 and CYP2D6 substrates in the individuals genotyped as poor metabolizers often significantly differentiates from the pharmacokinetics in the individuals belonging to other phenotype groups. Between the other phenotype groups the pharmacokinetic variability caused by the genotype seems to be often covered by other reasons causing variability in the pharmacokinetics. The pharmaceutical industry could benefit from methods that could predict the interindividual variability in the drug responses before the clinical studies. The pharmacokinetic variability caused by the genetic polymorphism of CYP enzymes has been predicted with different kinds of static and dynamic physiologically based pharmacokinetic simulation models. The models have taken the CYP genotype into account by non-substratespesific or substratespesific methods. The models have succeeded to predict the clinically observed interindividual variability in the pharmacokinetics of substrates. The goal of this study was to find out if in vitro metabolism data obtained with human liver microsomes genotyped for CYP2C19 or CYP2D6 could be used to predict the interindividual variability in the pharmacokinetics of drugs. The effect of polymorphism on metabolism was examined by incubating the substrates with microsomes with different CYP2C19 or CYP2D6 genotypes. S-mephenytoin, omeprazole and Y1 (compound developed by the pharmaceutical company Orion Oyj) were used as substrates for CYP2C19. Neither the rate of metabolism of S-mephenytoin nor omeprazole appeared to be dependent on the CYP2C19 genotype, with the exception of the poor metabolizer genotype. Use of microsomes genotyped for the other CYP2C19 phenotypes to obtain predictive in vitro metabolism data might therefore not be reasonable. More significant dependence of the Y1 metabolism on the CYP2C19 genotype could not be completely excluded. When examining the effect of polymorphism on non-selective metabolic reactions, the activity of metabolizing enzymes other than the polymorphic enzyme should always be taken into consideration: in this study, CYP3A4 activity biased the results initially achieved with omeprazole and Y1. Dextromethorphan and bufuralol were used as substrates for CYP2D6 and their rates of metabolism correlated well with the CYP2D6 genotype. So microsomes genotyped for CYP2D6 could possibly be used to obtain predictive in vitro metabolism data. If genotyped microsomes are to be used in the pharmaceutical industry to predict the interindividual variability in the pharmacokinetics, factors increasing reliability of the results should be considered first and more studies should be conducted.