Research ArticlesInvolvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol
Section snippets
Abbreviations:
- OATP
organic anion transporting polypeptide
- P-gp
P-glycoprotein
- FD-4
FITC-dextran (Mw 4000)
- IS
internal standard
- E3S
estrone-3-sulfate
- BSP
bromosulfophthalein
INTRODUCTION
β-Blockers have been clinically used for the treatment of various types of cardiovascular diseases including hypertension, myocardial infarction, angina pectoris and arrhythmia. They are also recently prescribed for chronic heart failure, although such application is still under the clinical trial in Japan.1,2 In most cases, β-blockers are orally administered to the patients because of their adequate absorption. The mechanism for the gastrointestinal absorption of β-blockers has not yet been
Materials
Celiprolol hydrochloride was a gift from Nichi-iko Pharmaceutical Co., Ltd. (Toyama, Japan). [3H]Estrone-3-sulfate (E3S) ammonium salt (1.59 TBq/mmol) was purchased from PerkinElmer Life and Analytical Sciences, Inc. (Boston, MA). The pcDNA3 vector was obtained from Invitrogen (Carlsbad, CA). FITC-dextran with an average molecular weight of 4000 (FD-4) was purchased from Sigma–Aldrich Inc. (St. Louis, MO). All other reagents were commercial products of reagent grade.
Animals
Six- to 8-week-old male
Comparison of Plasma Concentration Profile of Celiprolol After Oral Administration Between Wild and mdr1a/b(−/−) Mice
Involvement of P-gp as an efflux transport system for celiprolol has already been suggested by using P-gp inhibitor in rats,6 but there has been no direct demonstration using gene knockout mice. Therefore, we first compared plasma concentration profile of celiprolol after oral administration between wild and mdr1a/b(−/−) mice. In wild mice, plasma concentration of celiprolol after oral administration at 3 mg/kg was under the limit of quantification (<3 ng/mL) at most of sampling points, whereas
DISCUSSION
Possible involvement of influx transporters in gastrointestinal absorption has recently been suggested for several therapeutic agents. Especially, both OATP-A and OATP-B are expressed on apical membrane of small intestine in human and proposed to be involved in uptake of several anionic compounds.18,19,23 On the other hand, molecular mechanism involved in uptake of β-blockers from apical side has not yet been identified despite that they have been widely used as oral drugs. Recent observation
ACKNOWLEDGEMENTS
We thank Ms Lica Ishida for technical assistance for performing LC/MS/MS determination. We also thank Prof. Takaaki Abe in Tohoku University Graduate School of Medicine for kindly supplying pGEMHE vector. This study was supported in part by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.
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2017, Journal of Pharmaceutical SciencesCitation Excerpt :For example, significant uptake of celiprolol was observed in OATP2B1-expressing oocytes compared with water-injected oocytes,46 indicating celiprolol as a substrate of OATP2B1. In the same system, celiprolol was also found to be a substrate of OATP1A2 with a Km value of 20.5 μM.99 Based on these in vitro evidences, clinical interactions of celiprolol with orange juice and grapefruit juice are likely explained by intestinal inhibition of OATPs.
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