Severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency: First case presentation showing competition for excretion via renal multidrug resistance protein 1 and organic cation transporter 2

Abstract

A 72-year-old woman with renal insufficiency who was taking oral pilsicainide (150 mg/d) complained of feeling faint 3 days after she was prescribed oral cetirizine (20 mg/d). She was found to have a wide QRS wave with bradycardia. Her symptoms were relieved by termination of pilsicainide. The plasma concentrations of both drugs were significantly increased during the coadministration, and the cetirizine concentration decreased on cessation of pilsicainide despite the fact that treatment with cetirizine was continued, which suggested that the fainting was induced by the pharmacokinetic drug interaction. A pharmacokinetic study in 6 healthy male volunteers after a single dose of either cetirizine (20 mg) or pilsicainide (50 mg), or both, found that the renal clearance of each drug was significantly decreased by the coadministration of the drugs (from 475 +/- 101 mL/min to 279 +/- 117 mL/min for pilsicainide and from 189 +/- 37 mL/min to 118 +/- 28 mL/min for cetirizine; P = .008 and .009, respectively). In vitro studies using Xenopus oocytes with microinjected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 revealed that the transport of the substrates of these transporters was inhibited by either cetirizine or pilsicainide. Thus elevated concentrations of these drugs as a result of a pharmacokinetic drug-drug interaction via either human multidrug resistance protein 1 or human organic cation transporter 2 (or both) in the renal tubular cells might have caused the arrhythmia in our patient. Although cetirizine has less potential for causing arrhythmias than other histamine 1 blockers, such an interaction should be considered, especially in patients with renal insufficiency who are receiving pilsicainide.

Drug interactions

“…The mechanism of the reported renal interaction of the combination of cetirizine and pilsicainide in an elderly woman with renal insufficiency was claimed to be due to an interaction with P-gp and OCT2, as proposed by Tsuruoka et al (2006); however, in vitro studies with the human transport proteins have failed to show inhibitory properties for cetirizine or its enantiomers at therapeutic concentations. Indeed, several studies suggest different elimination mechanisms for pilsicainide and cetirizine .…”

Quantitation of pilsicainide in microscale samples of human biological fluids using liquid chromatography–tandem mass spectrometry

“…We previously reported that PLC is excreted via the organic cationic transport system in the renal proximal tubule in humans [8] and the elimination of PLC was not inhibited by verapamil, a potent P-glycoprotein inhibitor, in human and experimental studies [9]. In contrast, Tsuruoka et al [10] suggested that the excretion of PLC in the kidney is mediated by human multidrug resistance protein 1 based on the results of a pharmacokinetic drug-drug interaction study of PLC. Moreover, a case report suggested that the metabolic rate of PLC was increased by cytochrome p450 induction [11].…”

“…1, and ions at 273 → 110 and 325 → 79, respectively, were selected for subsequent quantitative analysis. The calibration curve for PLC ranged from 5 to 2000 ng/mL in human plasma, from 5 to 500 ng/mL in ultrafiltered plasma solution, and from 25 to 2000 ng/mL in urine, which were the concentration ranges of PLC in biological fluids in previous reports [7][8][9][10]. In addition, a LLOQ was obtained by simple extraction procedure using diethylether.…”

Facteurs à prendre en considération pour la gestion des interactions médicamenteuses en pratique clinique

“…Il est aussi difficile pour un praticien de suspecter et/ou de repé rer dans un article les limites du plan expé rimental, des erreurs de calcul et d'unité s et des dé saccords avec les ré sultats d'autres travaux, l'ensemble pouvant remettre en cause les conclusions du travail pré senté . C'est le cas de l'é tude rapportant une arythmie sé vè re due à l'interaction entre le pilsicainide et la cetirizine[54,55]. libellé officiel qui donne parfois un faible é clairage sur les risques encourus Au niveau de l'Afssaps, la mé thodologie qui guide l'inté gration et la non-inté gration des interactions dans le thé saurus est dé crite et accessible sur le site Internet de cet organisme.…”