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Titolo:
Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels
Autore:
Kuryshev, YA; Brown, AM; Wang, L; Benedict, CR; Rampe, D;
Indirizzi:
Aventis Pharmaceut Inc, Bridgewater, NJ 08807 USA Aventis Pharmaceut Inc Bridgewater NJ USA 08807 Bridgewater, NJ 08807 USA ChanTest Inc, Cleveland, OH USA ChanTest Inc Cleveland OH USAChanTest Inc, Cleveland, OH USA Case Western Reserve Univ, Rammelkamp Ctr Educ & Res, Cleveland, OH 44106 USA Case Western Reserve Univ Cleveland OH USA 44106 Cleveland, OH 44106 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 295, anno: 2000,
pagine: 614 - 620
SICI:
0022-3565(200011)295:2<614:IOT53A>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
INTRAVENOUS DOLASETRON MESYLATE; POTASSIUM CHANNEL; SODIUM-CHANNELS; GRANISETRON; BLOCK; ONDANSETRON; HERG; PHARMACOKINETICS; VOLUNTEERS; METABOLITE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Rampe, D Aventis Pharmaceut Inc, Route 202-206,POB 6800, Bridgewater, NJ 08807 USA Aventis Pharmaceut Inc Route 202-206,POB 6800 Bridgewater NJ USA 08807
Citazione:
Y.A. Kuryshev et al., "Interactions of the 5-hydroxytryptamine 3 antagonist class of antiemetic drugs with human cardiac ion channels", J PHARM EXP, 295(2), 2000, pp. 614-620

Abstract

Administration of the 5-hydroxytryptamine 3 receptor class of antiemetic agents has been associated with prolongation in the QRS, JT, and QT intervals of the ECG. To explore the mechanisms underlying these findings, we examined the effects of granisetron, ondansetron, dolasetron, and the active metabolite of dolasetron MDL 74,156 on the cloned human cardiac Na+ channel hH1 and the human cardiac K+ channel HERG and the slow delayed rectifier K+ channel KvLQT1/minK. Using patch-clamp electrophysiology we found that all of the drugs blocked Na+ channels in a frequency-dependent manner. At a frequency of 3 Hz, the IC50 values for block of Na+ current measured 2.6, 88.5,38.0, and 8.5 muM for granisetron, ondansetron, dolasetron, and MDL 74,156, respectively. Block was relieved by strong hyperpolarizing potentials, suggesting a possible interaction with an inactivated channel state. Recoveryfrom inactivation was impaired at -80 mV compared with -100 mV, and the fractional recovery was impaired by drug in a concentration-dependent manner. IC50 values for block of the HERG cardiac K+ channel measured 3.73, 0.81, 5.95, and 12.1 mM for granisetron, ondansetron, dolasetron, and MDL 74,156,respectively. Ondansetron (3 muM) also slowed decay of HERG tail currents. In contrast, none of these drugs (10 muM) produced greater than 30% block of the slow delayed rectifier K+ channel KvLQT1/minK. We concluded that theantiemetic agents tested in this study block human cardiac Na+ channels probably by interacting with the inactivated state. This may lead to clinically relevant Na+ channel blockade, especially when high heart rates or depolarized/ischemic tissue is present. The submicromolar affinity of ondansetron for the HERG K+ channel likely underlies the prolongation of cardiac repolarization reported for this drug.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/09/20 alle ore 12:35:39