Browsing by Subject "DRUG-DRUG INTERACTIONS"

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  • Kahma, Helinä; Aurinsalo, Laura; Neuvonen, Mikko; Katajamäki, Jani; Paludetto, Marie-Noelle; Viinamäki, Jenni; Launiainen, Terhi; Filppula, Anne M.; Tornio, Aleksi; Niemi, Mikko; Backman, Janne T. (2021)
    We developed an in vitro high-throughput cocktail assay with nine major drug-metabolizing CYP enzymes, optimized for screening of time-dependent inhibition. The method was applied to determine the selectivity of the time-dependent CYP2C8 inhibitors gemfibrozil 1-O-beta-glucuronide and clopidogrel acyl-beta-D-glucuronide. In vitro incubations with CYP selective probe substrates and pooled human liver microsomes were conducted in 96-well plates with automated liquid handler techniques and metabolite concentrations were measured with quantitative UHPLC-MS/MS analysis. After determination of inter-substrate interactions and Km values for each reaction, probe substrates were divided into cocktails I (tacrine/CYP1A2, bupropion/CYP2B6, amodiaquine/CYP2C8, tolbutamide/CYP2C9 and midazolam/CYP3A4/5) and II (coumarin/CYP2A6, S-mephenytoin/CYP2C19, dextromethorphan/CYP2D6 and astemizole/CYP2J2). Time-dependent inhibitors (furafylline/CYP1A2, selegiline/ CYP2A6, clopidogrel/CYP2B6, gemfibrozil 1-O-beta-glucuronide/CYP2C8, tienilic acid/CYP2C9, ticlopidine/ CYP2C19, paroxetine/CYP2D6 and ritonavir/CYP3A) and direct inhibitor (terfenadine/CYP2J2) showed similar inhibition with single substrate and cocktail methods. Established time-dependent inhibitors caused IC50 fold shifts ranging from 2.2 to 30 with the cocktail method. Under time-dependent inhibition conditions, gemfibrozil 1-O-beta-glucuronide was a strong (90% inhibition) and selective (<< 20% inhibition of other CYPs) inhibitor of CYP2C8 at concentrations ranging from 60 to 300 mu M, while the selectivity of clopidogrel acyl-beta-D-glucuronide was limited at concentrations above its IC80 for CYP2C8. The time-dependent IC50 values of these glucuronides for CYP2C8 were 8.1 and 38 mu M, respectively. In conclusion, a reliable cocktail method including the nine most important drug-metabolizing CYP enzymes was developed, optimized and validated for detecting timedependent inhibition. Moreover, gemfibrozil 1-O-beta-glucuronide was established as a selective inhibitor of CYP2C8 for use as a diagnostic inhibitor in in vitro studies.
  • Itkonen, Matti K.; Tornio, Aleksi; Filppula, Anne M.; Neuvonen, Mikko; Neuvonen, Pertti J.; Niemi, Mikko; Backman, Janne T. (2018)
    The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.
  • Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Tapaninen, Tuija; Paile-Hyvärinen, Maria; Kärjä, Vesa; Männistö, Ville T.; Pihlajamäki, Jussi; Backman, Janne T.; Niemi, Mikko (2018)
    To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC(0-)) of montelukast (by 18% per copy of the minor allele; P=1.83 x 10(-10)). UGT1A3*2 was associated with increased AUC(0-) of montelukast acyl-glucuronide M1 and decreased AUC(0-) of hydroxymetabolites M5R, M5S, and M6 (P <10(-9)). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC(0-) of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC(0-) of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers.
  • Bobrova, Veera; Heinamäki, Jyrki; Honkanen, Outi; Desselle, Shane; Airaksinen, Marja; Volmer, Daisy (2019)
    Background: Multi-dose dispensing (MDD) of medications is a health technology designed to promote medication adherence and patient safety. MDD has been used as an alternative to ordinary prescription dispensing for patients, mostly elderly with high medication use. Objective: To evaluate the initiation phase of the MDD service to older adults >= 65 years and assess wheter the medication use of the new MDD patients is appropriate in terms of drug related problems. Methods: The European Union EU(7)-PIM list and the Inxbase databases were used for identifying potentially inappropriate medications (PIMs) and drug-drug interactions (DDIs). The study sample consisted of a total of 208 patients aged 65-108 years who were involved in the MDD service (PharmaService Ltd.) in Finland in 2015-2016. Clinically significant differences of PIM and DDI occurrences were identified using a Pearson's chi-square test throughout the demographic groups under study. Results: Results demonstrate that for 81% of the study participants, at least one medication from the EU (7)-PIM list was prescribed, and up to 64% of PIMs were clinically significant. According to the Inxbase database, five patients (2.4%) were prescribed category D clinically significant DDIs. Additionally, 61% of the patients saw an increase in the number of medications prescribed within six months after the initial MDD order. Conclusions: The results suggest that the MDD service should be accompanied by a regular medication review tailored to specific patient groups (i.e., older patients) to avoid potential DRPs.