Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption

Horie, Asuka; Ishida, Kazuya; Shibata, Katsunari; Taguchi, Masato; Ozawa, Ayaka; Hirono, Keiichi; Ichida, Fukiko; Hashimoto, Yoshiaki

doi:10.1002/bdd.1877

Cited by 14 publications

(9 citation statements)

References 24 publications

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“…All the STDD NMR samples contained 1 µM Pgp reconstituted into liposomes in 80% deuterated 100 mM KPi buffer, pD 7.4. For the STDD NMR experiments, a saturation transfer difference (STD) pulse sequence was used with a WATERGATE pulse sequence to suppress background water [46], with a 30 ms T1ρ spin lock filter to suppress background NMR signals and a train of 50 ms gaussian shaped selective pulses to excite the protein [47]. A total of 512 off-resonance spectra were subtracted from on-resonance spectra within the pulse program with a 2 sec saturation pulse by phase cycling at 40 and −1.5 ppm, respectively.…”

Section: Methodsmentioning

confidence: 99%

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Ledwitch

Gibbs

Barnes

et al. 2016

Biochemical Pharmacology

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The P-glycoprotein (Pgp) transporter plays a central role in drug disposition by effluxing a chemically diverse range of drugs from cells through conformational changes and ATP hydrolysis. A number of drugs are known to activate ATP hydrolysis of Pgp, but coupling between ATP and drug binding is not well understood. The cardiovascular drug verapamil is one of the most widely studied Pgp substrates and therefore, represents an ideal drug to investigate the drug-induced ATPase activation of Pgp. As previously noted, verapamil-induced Pgp-mediated ATP hydrolysis kinetics was biphasic at saturating ATP concentrations. However, at subsaturating ATP concentrations, verapamil-induced ATPase activation kinetics became monophasic. To further understand this switch in kinetic behavior, the Pgp-coupled ATPase activity kinetics was checked with a panel of verapamil and ATP concentrations and fit with the substrate inhibition equation and the kinetic fitting software COPASI. The fits suggested that cooperativity between ATP and verapamil switched between low and high verapamil concentration. Fluorescence spectroscopy of Pgp revealed that cooperativity between verapamil and a non-hydrolyzable ATP analog leads to distinct global conformational changes of Pgp. NMR of Pgp reconstituted in liposomes showed that cooperativity between verapamil and the non-hydrolyzable ATP analog modulate each others interactions. This information was used to produce a conformationally-gated model of drug-induced activation of Pgp-mediated ATP hydrolysis.

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Section: Methodsmentioning

confidence: 99%

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Ledwitch

Gibbs

Barnes

et al. 2016

Biochemical Pharmacology

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“…Moreover, a large interindividual variability in systemic clearance and bioavailability of flecainide has been reported. This can be attributed to the genetic polymorphisms of CYP2D6, which metabolizes the drug in the liver, but also to functional variability in the transporters in the kidney (P-glycoprotein) and intestine (H+/tertiary amine antiporter) [13]. As far as median elimination half-life is concerned, Till et al described a significant linear correlation between elimination half-life of flecainide and age (r = 0.75; p < 0.01), both in case of oral and intravenous treatment [14].…”

Section: Discussionmentioning

confidence: 99%

Incessant Automatic Atrial Tachycardia in a Neonate Successfully Treated with Nadolol and Closely Spaced Doses of Flecainide: A Case Report

et al. 2020

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Supraventricular tachyarrhythmia (SVT) is the most common type of arrhythmia in childhood. Management can be challenging with an associated risk of mortality. A female neonate was diagnosed with episodes of SVT, controlled antenatally with digoxin. Flecainide was commenced prophylactically at birth. Despite treatment, the infant developed a narrow complex tachycardia at 5 days of age. The electrocardiogram features were suggestive of either re-entry tachycardia or of automatic atrial tachycardia (AAT). Following several unsuccessful treatments, a wide complex tachycardia developed. A transesophageal electrophysiological study led to a diagnosis of AAT. Stable sinus rhythm was finally achieved through increasing daily administrations of flecainide up to six times a day, in association with nadolol. The shortening of intervals to this extent has never been reported before and supports the evidence of a personal, age-specific variability in pharmacokinetics of flecainide. Larger studies are needed to better define the appropriate dose and timing of administration.

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“…Drug transporters mediate active renal tubular secretion through uptake in the basolateral membrane and efflux in the apical membrane of renal proximal tubules. 5) A previous in vitro study has reported that renal excretion of flecainide is associated with multidrug resistance protein 1 (MDR1) in the renal tubule. 6) Although organic cation transporter (OCT) 2 for basolateral uptake and multidrug and toxin extrusion (MATE) 1 and MATE2-K for apical efflux are also involved in the renal tubular secretion of cationic drugs, 5) the contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide, a cationic drug, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…5) A previous in vitro study has reported that renal excretion of flecainide is associated with multidrug resistance protein 1 (MDR1) in the renal tubule. 6) Although organic cation transporter (OCT) 2 for basolateral uptake and multidrug and toxin extrusion (MATE) 1 and MATE2-K for apical efflux are also involved in the renal tubular secretion of cationic drugs, 5) the contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide, a cationic drug, remains unclear. Because drug-drug interactions in renal excretion of flecainide may involve the inhibition of renal uptake and efflux transporters, it is important to understand the involvement of these transporters in renal tubular secretion of flecainide.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide

Doki

Apáti

Sakata

et al. 2019

Biological & Pharmaceutical Bulletin

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Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC 50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2-and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 23.9 vs. 11.8 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of flecainide. However, in vivo drug-drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

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Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption

Cited by 14 publications

References 24 publications

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein

Incessant Automatic Atrial Tachycardia in a Neonate Successfully Treated with Nadolol and Closely Spaced Doses of Flecainide: A Case Report

Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide

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