Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

Keywords:
Carvedilol, Citalopram, Pharmacokinetics, Cytochrome P450, Preclinical study, Rat liver microsomes, Enzyme inhibition
1.
Dulin B, Abraham WT: Pharmacology of carvedilol. Am J Cardiol 2004;93:3B-6B.
2.
Cullington D, Yassin A, Cleland J: Beta-blockers in the treatment of cardiovascular disease. Prescriber 2008;19:31-39.
3.
Vanhoutte PM, Gao Y: Beta blockers, nitric oxide, and cardiovascular disease. Curr Opin Pharmacol 2013;13:265-273.
4.
Morgan T: Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet 1994;26:335-346.
5.
Ishida K, Taira S, Morishita H, Kayano Y, Taguchi M, Hashimoto Y: Stereoselective oxidation and glucuronidation of carvedilol in human liver and intestinal microsomes. Biol Pharm Bull 2008;31:1297-1300.
6.
Oldham HG, Clarke SE: In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol. Drug Metab Dispos 1997;25:970-977.
7.
Stafylas PC, Sarafidis PA: Carvedilol in hypertension treatment. Vasc Health Risk Manag 2008;4:23-30.
8.
Rao N: The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 2007;46:281-290.
9.
von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Venkatakrishnan K, Duan SX, Fogelman SM, Harmatz JS, Shader RI: Citalopram and desmethylcitalopram in vitro: human cytochromes mediating transformation, and cytochrome inhibitory effects. Biol Psychiatry 1999;46:839-849.
10.
Kobayashi K, Chiba K, Yagi T, Shimada N, Taniguchi T, Horie T, Tani M, Yamamoto T, Ishizaki T, Kuroiwa Y: Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes. J Pharmacol Exp Ther 1997;280:927-933.
11.
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm (accessed on April 5, 2017).
12.
Noehr-Jensen L, Zwisler ST, Larsen F, Sindrup SH, Damkier P, Brosen K: Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain. Clin Pharmacol Ther 2009;86:626-633.
13.
Jeppesen U, Gram LF, Vistisen K, Loft S, Poulsen HE, Brøsen K: Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J Clin Pharmacol 1996;51:73-78.
14.
Brøsen K, Naranjo CA: Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 2001;11:275-283.
15.
Spina E, Santoro V, DʼArrigo C: Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 2008;30:1206-1227.
16.
Caccia S: Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998;34:281-302.
17.
Kremers P, Beaune P, Cresteil T, de Graeve J, Columelli S, Leroux JP, Gielen JE: Cytochrome P-450 Monooxygenase Activities in Human and Rat Liver Microsomes. Eur J Biochem 1981;118:599-606.
18.
Gheldiu AM, Popa DS, Loghin F, Vlase L: Oxidative metabolism of estrone modified by genistein and bisphenol A in rat liver microsomes. Biomed Environ Sci 2015;28:834-838.
19.
Cotreau MM, von Moltke LL, Beinfeld MC, Greenblatt DJ: Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level. J Pharmacol Toxicol Methods 2000;43:41-54.
20.
Butnariu A, Popa DS, Vlase L, Andreica M, Muntean D, Leucuţa S: New high-throughput liquid chromatographic tandem mass spectrometry assay for therapeutic drug monitoring of carvedilol in children with congestive heart failure. Rev Romana Med Lab 2009;15:7-15.
21.
Lynch T, Price A: The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007;76:391-396.
22.
Meyer UA: Pharmacogenetics and adverse drug reactions. Lancet 2000;356:1667-1671.
23.
Martignoni M, Groothuis GM, de Kanter R: Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006;2:875-894.
24.
Venhorst J, Ter Laak AM, Commandeur JN, Funae Y, Hiroi T, Vermeulen NP: Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities. J Med Chem 2003;46:74-86.
25.
Huffman JC, Celano CM, Beach SR, Motiwala SR, Januzzi JL: Depression and cardiac disease: epidemiology, mechanisms, and diagnosis. Cardiovasc Psychiatry Neurol 2013;2013:695925.
26.
Katon WJ: Clinical and health services relationships between major depression, depressive symptoms, and general medical illness. Biol Psychiatry 2003;54:216-226.
27.
Scalco AZ, Scalco MZ, Azul JB, Neto FL: Hypertension and depression. Clinics 2005;60:241-250.
28.
Hare DL, Toukhsati SR, Johansson P, Jaarsma T: Depression and cardiovascular disease: a clinical review. Eur Heart J 2014;35:1365-1372.
29.
Thomas SA, Chapa DW, Friedmann E, Durden C, Ross A, Lee MC, Lee HJ: Depression in patients with heart failure: prevalence, pathophysiological mechanisms, and treatment. Crit Care Nurse 2008;28:40-55.
30.
Wang L, Wang S, Chen M, Chen X, Lin Y, Hu X, Huang X, Li X, Hu G: Inhibitory effect of ketoconazole and voriconazole on the pharmacokinetics of carvedilol in rats. Drug Dev Ind Pharm 2015;41:1661-1666.
31.
Lim TH, Cho YA, Choi DH: Effects of cilostazol on the pharmacokinetics of carvedilol after oral and intravenous administration in rats. J Physiol Pharmacol 2015;66:591-597.
32.
Choi JS, Choi DH: Pharmacokinetic drug interaction between carvedilol and ticlopidine in rats. Biomol Ther 2010;18:343-349.
33.
Lee CK, Choi JS: Effects of glipizide on the pharmacokinetics of carvedilol after oral and intravenous administration in rats. Biomol Ther 2011;19:237-242.
34.
Abrudan MB, Muntean DM, Gheldiu AM, Neag MA, Vlase L: The pharmacokinetic interaction study between carvedilol and bupropion in rats. Pharmacology 2017;99:139-143.
35.
Graff DW, Williamson KM, Pieper JA, Carson SW, Adams KF Jr, Cascio WE, Patterson JH: Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients. J Clin Pharmacol 2001;41:97-106.
36.
Stout SM, Nielsen J, Bleske BE, Shea M, Brook R, Kerber K, Welage LS: The impact of paroxetine coadministration on stereospecific carvedilol pharmacokinetics. J Cardiovasc Pharmacol Ther 2010;15:373-379.
37.
Briciu C, Neag M, Muntean D, Vlase L, Bocsan C, Buzoianu A, Gheldiu AM, Achim M, Popa A: A pharmacokinetic drug interaction study between nebivolol and duloxetine. Exp Clin Cardiol 2014;20:1374-1379.
38.
Briciu C, Neag M, Muntean D, Vlase L, Bocsan C, Buzoianu A, Gheldiu AM, Achim M, Popa A: A pharmacokinetic drug interaction study between nebivolol and paroxetine in healthy volunteers. J Clin Pharm Ther 2014;39:535-540.
39.
Gheldiu AM, Popa A, Neag M, Muntean D, Bocsan C, Buzoianu A, Vlase L, Tomuta I, Briciu C: Assessment of a potential pharmacokinetic interaction between nebivolol and bupropion in healthy volunteers. Pharmacology 2016;98:190-198.
40.
Kilickiran-Avci B, Oto A: Preferred beta-blockers for the treatment of heart failure. Eur J Cardiol Practice 2006;13:9.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.