Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

doi:10.1002/jps.21618

Journal of Pharmaceutical Sciences

Volume 98, Issue 7, July 2009, Pages 2529-2539

https://doi.org/10.1002/jps.21618 Get rights and content

ABSTRACT:

Gastrointestinal absorption of several β-blockers is inhibited by citrus juices, although molecular mechanism(s) lying on their small intestinal absorption has not yet been identified. Here, we attempted to demonstrate involvement of both influx and efflux transporters in vivo in gastrointestinal absorption of celiprolol in mice. Plasma concentration of celiprolol (3 mg/kg) after oral administration was mostly under the limit of quantification in wild mice, whereas that in mdr1a/b knockout (mdr1a/b^(−/−)) mice was much more obvious, indicating P-glycoprotein-mediated efflux. Then, the oral absorption of celiprolol in mdr1a/b^(−/−) mice was further examined to investigate influx transport mechanism with avoiding effect of P-glycoprotein. Coadministration of bromosulfophthalein (BSP), an inhibitor of various influx transporters including organic anion transporting polypeptide (OATP) reduced plasma celiprolol concentration. Inhibition by BSP of celiprolol uptake from apical membranes was confirmed in Ussing-type chamber of small intestinal tissues. Uptake of celiprolol by human small intestinal transporter OATP-A/1A2 was also confirmed in Xenopus Laevis oocytes. Interestingly, OATP-A/1A2 accepts various β-blockers including acebutolol, atenolol and sotalol, oral absorption of which is inhibited by coadministration of citrus juice or telithromycin in human. Taken together, these findings have suggested fundamental role of influx transport system(s) in oral absorption of celiprolol. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2529–2539, 2009

Section snippets

Abbreviations:

OATP

organic anion transporting polypeptide

P-gp

P-glycoprotein

FD-4

FITC-dextran (Mw 4000)

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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Research ArticlesInvolvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

ABSTRACT:

Section snippets

Abbreviations:

INTRODUCTION

Materials

Animals

Comparison of Plasma Concentration Profile of Celiprolol After Oral Administration Between Wild and mdr1a/b(−/−) Mice

DISCUSSION

ACKNOWLEDGEMENTS

Am Heart J

J Pharm Sci

Biochem Biophys Res Commun

J Control Release

Biochim Biophys Acta

J Biol Chem

Pharmacological properties of beta-adrenoceptor blocking drugs

J Clin Bas Cardiol

The absorption of beta-adrenoceptor antagonists in rat in situ small intestine; the effect of lipophilicity

J Pharm Pharmacol

Dose-dependent acebutolol disposition after oral administration

Clin Pharmacol Ther

Celiprolol: Pharmacokinetics and duration of pharmacodynamic activity

Br J Clin Pract Suppl

Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier

J Pharm Pharmacol

Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats

Drug Metab Dispos

Transport of celiprolol across human intestinal epithelial (Caco-2) cells: Mediation of secretion by multiple transporters including P-glycoprotein

Br J Pharmacol

A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells

Pharm Res

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

Clin Pharmacol Ther

Effects of grapefruit juice on the pharmacokinetics of acebutolol

Br J Clin Pharmacol

Effects of orange juice on the pharmacokinetics of atenolol

Eur J Clin Pharmacol

Grapefruit juice ingestion significantly reduces talinolol bioavailability

Clin Pharmacol Ther

Orange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol

Clin Pharmacol Ther

Research Articles
Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

Comparison of Plasma Concentration Profile of Celiprolol After Oral Administration Between Wild and mdr1a/b^(−/−) Mice