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Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.

التفاصيل البيبلوغرافية
العنوان: Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.
المؤلفون: Hirvensalo P; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Tornio A; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Tapaninen T; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Paile-Hyvärinen M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Neuvonen M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Backman JT; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Niemi M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
المصدر: Clinical and translational science [Clin Transl Sci] 2022 Feb; Vol. 15 (2), pp. 409-421. Date of Electronic Publication: 2021 Sep 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: WileyBlackwell Pub Country of Publication: United States NLM ID: 101474067 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-8062 (Electronic) Linking ISSN: 17528054 NLM ISO Abbreviation: Clin Transl Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Malden, MA : WileyBlackwell Pub., 2008-
مواضيع طبية MeSH: Celiprolol*/pharmacokinetics , Organic Anion Transporters*/metabolism, ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Genotype ; Humans ; Pharmacogenetics ; Polymorphism, Single Nucleotide
مستخلص: The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC 0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC 0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC 0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC 0-∞ in the high exposure group (p = 1.08 × 10 -11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC 0-∞ (p < 5 × 10 -6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.
(© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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معلومات مُعتمدة: Sigrid Jusélius Foundation; Biomedicum Helsinki Foundation; Orion Research Foundation; 282106 International ERC_ European Research Council
المشرفين على المادة: 0 (ABCB1 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily B)
0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
0 (Organic Anion Transporters)
0 (SLCO1A2 protein, human)
DRB57K47QC (Celiprolol)
تواريخ الأحداث: Date Created: 20210929 Date Completed: 20220316 Latest Revision: 20220531
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8841435
DOI: 10.1111/cts.13159
PMID: 34585840
قاعدة البيانات: MEDLINE
الوصف
تدمد:1752-8062
DOI:10.1111/cts.13159