| 1. |
- Itkonen, Matti K., et al.
(author)
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Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans
- 2018
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In: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 104:3, s. 495-504
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Männistö, Ville, et al.
(author)
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Protein Phosphatase 1 Regulatory Subunit 3B Genotype at rs4240624 Has a Major Effect on Gallbladder Bile Composition
- 2021
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In: Hepatology Communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 5, s. 244-257
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Journal article (peer-reviewed)abstract
- The protein phosphatase 1 regulatory subunit 3B (PPP1R3B) gene is a target of farnesoid X receptor (FXR), which is a major regulator of bile acid metabolism. Both PPP1R3B and FXR have been suggested to take part in glycogen metabolism, which may explain the association of PPP1R3B gene variants with altered hepatic computed tomography attenuation. We analyzed the effect of PPP1R3B rs4240624 variant on bile acid composition in individuals with obesity. The study cohort consisted of 242 individuals from the Kuopio Obesity Surgery Study (73 men, 169 women, age 47.6±9.0years, body mass index 43.2±5.4kg/m2) with PPP1R3B genotype and liver RNA sequencing (RNA-seq) data available. Fasting plasma and gallbladder bile samples were collected from 50 individuals. Bile acids in plasma did not differ based on the PPP1R3B rs4240624 genotype. However, the concentration of total bile acids (109±55 vs. 35±19mM; P=1.0×10−5) and all individual bile acids (also 7α-hydroxy-4-cholesten-3-one [C4]) measured from bile were significantly lower in those with the AG genotype compared to those with the AA genotype. In addition, total cholesterol (P=0.011) and phospholipid (P=0.001) levels were lower in individuals with the AG genotype, but cholesterol saturation index did not differ, indicating that the decrease in cholesterol and phospholipid levels was secondary to the change in bile acids. Liver RNA-seq data demonstrated that expression of PPP1R3B, tankyrase (TNKS), Homo sapiens chromosome 8 clone RP11-10A14.5 (AC022784.1 [LOC157273]), Homo sapiens chromosome 8 clone RP11-375N15.1 (AC021242.1), and Homo sapiens chromosome 8, clone RP11-10A14 (AC022784.6) associated with the PPP1R3B genotype. In addition, genes enriched in transmembrane transport and phospholipid binding pathways were associated with the genotype. Conclusion: The rs4240624 variant in PPP1R3B has a major effect on the composition of gallbladder bile. Other transcripts in the same loci may be important mediators of the variant effect.
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| 3. |
- Nummela, Aleksi, et al.
(author)
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Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine : a randomised controlled trial using tandem mass spectrometry
- 2022
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In: BJA Open. - : Elsevier. - 2772-6096. ; 4
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Journal article (peer-reviewed)abstract
- BackgroundThis exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection.MethodsIn this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n=40), propofol (1.7 μg ml−1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 μg ml−1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed.ResultsStatistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) –1.19 (–1.6; –0.78), P<0.001 and 12,13-DiHOME –1.22 (–1.66; –0.77), P<0.001 were affected. Propofol elevated 9,10-DiHOME 2.29 (1.62; 2.96), P<0.001 and 12,13-DiHOME 2.13 (1.42; 2.84), P<0.001. Analytes were mostly unaffected by S-ketamine. Sevoflurane decreased tauroursodeoxycholic acid (TUDCA) –2.7 (–3.84; –1.55), P=0.015.ConclusionsDexmedetomidine-induced oxylipin alterations may be connected to pathways associated with organ protection. In contrast to dexmedetomidine, propofol emulsion elevated DiHOMEs, oxylipins associated with acute respiratory distress syndrome, and mitochondrial dysfunction in high concentrations. Further research is needed to establish the behaviour of DIHOMEs during prolonged propofol/dexmedetomidine infusions and to verify the sevoflurane-induced reduction in TUDCA, a suggested neuroprotective agent.Clinical trial registrationNCT02624401.
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| 4. |
- Becquemont, Laurent, et al.
(author)
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Practical recommendations for pharmacogenomics-based prescription : 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics
- 2011
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In: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 12:1, s. 113-124
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Research review (peer-reviewed)abstract
- The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.
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| 5. |
- Cooper-DeHoff, Rhonda M., et al.
(author)
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The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms
- 2022
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In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 111:5, s. 1007-1021
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Journal article (peer-reviewed)abstract
- Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.
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| 6. |
- Enestam, Sonja, et al.
(author)
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Occurrence of zinc and lead in aerosols and deposits in the fluidized bed combustion of recovered waste wood : Part 1: Samples from boilers
- 2011
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In: Energy & Fuels. - : American Chemical Society. - 0887-0624 .- 1520-5029. ; 25:4, s. 1396-1404
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Journal article (peer-reviewed)abstract
- Combustion of recovered waste wood (RWW) has led to increased fouling and corrosion of furnace walls, superheaters, and economizers. These problems have been associated mainly with chlorine, zinc, and lead in the deposits but also with sodium and titanium. The presence of lead and zinc compounds, especially lead and zinc chlorides, has been shown to increase the corrosivity of the deposits even at relatively low metal temperatures (230−450 °C). The present work determined experimentally the distribution and speciation of zinc and lead compounds in aerosol particles and deposits in the fluidized-bed combustion of RWW. Measurements were conducted in both a full-scale (20 MWth) plant with as-received RWW and in a pilot-scale (2 MWth) setup with as-received RWW and RWW doped with zinc and lead. The results show that the amount and speciation of zinc and lead in the deposits vary depending upon the fuel composition, flue gas temperature, and metal temperature. Both lead and zinc chlorides are found in temperature ranges typical for the primary superheater area. A caracolite-type compound [Na3Pb2(SO4)3Cl] was identified in deposits from the economizer area and K2ZnCl4 in the sub-micrometer aerosol particle fraction.
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| 7. |
- Fanta, Samuel, et al.
(author)
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Long-Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children : Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism
- 2010
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In: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 50:5, s. 581-597
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Journal article (peer-reviewed)abstract
- To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose-interval curves. A 3-compartment population pharmacokinetic model was used to describe the data. Cyclosporine oral bioavailability increased more than 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1 to 1.5 years. Moreover, older children receiving cyclosporine twice daily as the gelatin capsule microemulsion formulation had an about 1.25 to 1.3 times higher bioavailability than did the younger children receiving the liquid formulation thrice daily. In 91 children with genetic data after transplantation, patients carrying the NR1I2 g.-25385C-g.-24381A-g.205_-200GAGAAG-g.7635G-g.8055C haplotype had about one-tenth lower bioavailability, per allele, than did non-carriers (P = .039). The significance of the NR1I2 genotype warrants further study. In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children.
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| 8. |
- Fanta, Samuel, et al.
(author)
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Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1 polymorphisms
- 2008
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In: Pharmacogenetics and genomics. - 1744-6872. ; 18:2, s. 77-90
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate whether variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes are associated with the pharmacokinetics of cyclosporine in pediatric renal transplant candidates, and whether the effects of these variants are related to age. METHODS: A total of 104 pediatric patients (aged 0.36-16.3 years) were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. The patients had undergone a pharmacokinetic study with intravenous and oral ciclosporine (INN, cyclosporin) before renal transplantation. RESULTS: In the whole population, the mean+/-SD cyclosporine oral bioavailability was 0.38+/-0.09, volume of distribution was 2.3+/-0.54 l/kg, and systemic clearance normalized by allometric body weight was 0.88+/-0.16 l/h/kg3/4. The prehepatic extraction ratio was 0.51+/-0.13, and the hepatic extraction ratio was 0.24+/-0.04, the former explaining 95% of the variability in oral bioavailability (P<0.0001). In children older than 8 years, the pre-hepatic extraction was 0.64+/-0.09 in those with the ABCB1 c.2677GG genotype, 0.52+/-0.11 in those with the c.2677GT genotype, and 0.41+/-0.03 in those with the c.2677TT genotype (P=0.021, r2=0.334), leading to corresponding differences in oral bioavailability (0.28+/-0.07, 0.36+/-0.07, and 0.44+/-0.04, respectively; P=0.012, r2=0.372). Similar associations were observed with the ABCB1 c.1236C>T variant and the related haplotype c.1199G-c.1236C-c.2677G-c.3435C (P<0.05). The estimated oral dose requirement and clearance of cyclosporine remained largely unexplained by the genetic variations. CONCLUSIONS: Although these data suggest an age-related effect of ABCB1 polymorphism on oral bioavailability, further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.
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| 9. |
- Häkkinen, Katja, et al.
(author)
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Functional characterization of six SLCO1B1 (OATP1B1) variants observed in Finnish individuals with a psychotic disorder
- 2023
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In: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 20:3, s. 1500-1508
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Journal article (peer-reviewed)abstract
- Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2′,7′-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.
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| 10. |
- Koskiniemi, Hanna, et al.
(author)
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Crystal structures of two aromatic hydroxylases involved in the early tailoring steps of angucycline biosynthesis
- 2007
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In: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836 .- 1089-8638. ; 372:3, s. 633-648
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Journal article (peer-reviewed)abstract
- Angucyclines are aromatic polyketides produced in Streptomycetes via complex enzymatic biosynthetic pathways. PgaE and CabE from S. sp PGA64 and S. sp. H021 are two related homo-dimeric FAD and NADPH dependent aromatic hydroxylases involved in the early steps of the angucycline core modification. Here we report the three-dimensional structures of these two enzymes determined by X-ray crystallography using multiple anomalous diffraction and molecular replacement, respectively, to resolutions of 1.8 A and 2.7 A. The enzyme subunits are built up of three domains, a FAD binding domain, a domain involved in substrate binding and a C-terminal thioredoxin-like domain of unknown function. The structure analysis identifies PgaE and CabE as members of the para-hydroxybenzoate hydroxylase (pHBH) fold family of aromatic hydroxylases. In contrast to phenol hydroxylase and 3-hydroxybenzoate hydroxylase that utilize the C-terminal domain for dimer formation, this domain is not part of the subunit-subunit interface in PgaE and CabE. Instead, dimer assembly occurs through interactions of their FAD binding domains. FAD is bound non-covalently in the "in"-conformation. The active sites in the two enzymes differ significantly from those of other aromatic hydroxylases. The volumes of the active site are significantly larger, as expected in view of the voluminous tetracyclic angucycline substrates. The structures further suggest that substrate binding and catalysis may involve dynamic rearrangements of the middle domain relative to the other two domains. Site-directed mutagenesis studies of putative catalytic groups in the active site of PgaE argue against enzyme-catalyzed substrate deprotonation as a step in catalysis. This is in contrast to pHBH, where deprotonation/protonation of the substrate has been suggested as an essential part of the enzymatic mechanism.
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