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 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.

Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers

“…Moreover, Hirvensalo et al . recently demonstrated that intestinal OATP1A2 and P‐glycoprotein play a role in the pharmacokinetics of celiprolol in humans, 42 further supporting the molecular mechanism underlying fexofenadine‐GT interaction through OATP1A2.…”

“…However, recent highly sensitive proteomic analyses reported the expression of OATP1A2 in human jejunum and ileum samples. 37,39 Moreover, Hirvensalo et al recently demonstrated that intestinal OATP1A2 and P-glycoprotein play a role in the pharmacokinetics of celiprolol in humans, 42 further supporting the molecular mechanism underlying fexofenadine-GT interaction through OATP1A2.…”

Sensitive detection of single-nucleotide polymorphisms by conjugated polymers for personalized treatment of hypertension

“…Previous studies have shown that endothelin-1 (EDN1) may alter responses to β-adrenergic blockers, especially because TT carriers at the G5665T locus have a poor prognosis after β-blocker therapy ( 38 , 39 ). Absorption of β-blockers is also influenced by the multidrug transporter P-glycoprotein [expressed by the adenosine triphosphate (ATP)–binding cassette subfamily B member 1 (ABCB1) gene], whose gene polymorphism is associated with reduced AUC (area under the curve) for the drug ( 40 , 41 ). In addition, voltage-gated calcium channel α1C (CACNA1C) polymorphisms are associated with antihypertensive efficacy.…”

Transporters in Drug Development: International Transporter Consortium Update on Emerging Transporters of Clinical Importance

“…Likewise, celiprolol has been proposed as a sensitive clinical OATP2B1 probe 49 with supporting pharmacogenomic data to suggest that SLCO2B1 polymorphism affects celiprolol pharmacokinetics (PK) at the therapeutic dose 53 . However, in vitro transport of celiprolol was also shown to be mediated by intestinal OATP1A2 54 and a recent pharmacogenomic study suggested a possible involvement of intestinal OATP1A2 and P‐gp in celiprolol pharmacokinetics in humans 55 . The relative contribution between OATP2B1 and OATP1A2 needs to be understood before celiprolol can be recommended as a clinical probe for OATP2B1.…”

“…53 However, in vitro transport of celiprolol was also shown to be mediated by intestinal OATP1A2 54 and a recent pharmacogenomic study suggested a possible involvement of intestinal OATP1A2 and P-gp in celiprolol pharmacokinetics in humans. 55 The relative contribution between OATP2B1 and OATP1A2 needs to be understood before celiprolol can be recommended as a clinical probe for OATP2B1.…”