Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics
Abstract 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 sin...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-02-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13159 |
| _version_ | 1818330618915717120 |
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| author | Päivi Hirvensalo Aleksi Tornio Tuija Tapaninen Maria Paile‐Hyvärinen Mikko Neuvonen Janne T. Backman Mikko Niemi |
| author_facet | Päivi Hirvensalo Aleksi Tornio Tuija Tapaninen Maria Paile‐Hyvärinen Mikko Neuvonen Janne T. Backman Mikko Niemi |
| author_sort | Päivi Hirvensalo |
| collection | DOAJ |
| description | Abstract 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 (AUC0–∞). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0–∞. 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 AUC0–∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0–∞ 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 AUC0–∞ (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. |
| first_indexed | 2024-12-13T13:06:49Z |
| format | Article |
| id | doaj.art-f35f6c69bf1d47e79c46e8a0f915094e |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-12-13T13:06:49Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-f35f6c69bf1d47e79c46e8a0f915094e2022-12-21T23:44:48ZengWileyClinical and Translational Science1752-80541752-80622022-02-0115240942110.1111/cts.13159Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokineticsPäivi Hirvensalo0Aleksi Tornio1Tuija Tapaninen2Maria Paile‐Hyvärinen3Mikko Neuvonen4Janne T. Backman5Mikko Niemi6Department of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandDepartment of Clinical Pharmacology University of Helsinki Helsinki FinlandAbstract 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 (AUC0–∞). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0–∞. 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 AUC0–∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0–∞ 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 AUC0–∞ (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.https://doi.org/10.1111/cts.13159 |
| spellingShingle | Päivi Hirvensalo Aleksi Tornio Tuija Tapaninen Maria Paile‐Hyvärinen Mikko Neuvonen Janne T. Backman Mikko Niemi Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics Clinical and Translational Science |
| title | Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics |
| title_full | Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics |
| title_fullStr | Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics |
| title_full_unstemmed | Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics |
| title_short | Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics |
| title_sort | pharmacogenomics of celiprolol evidence for a role of p glycoprotein and organic anion transporting polypeptide 1a2 in celiprolol pharmacokinetics |
| url | https://doi.org/10.1111/cts.13159 |
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