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Cardiovascular Research 2002 55(4):799-805; doi:10.1016/S0008-6363(02)00448-0
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Copyright © 2002, European Society of Cardiology

The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels

Mackenzi Mbai1, Sridharan Rajamani1 and Craig T January*

Department of Medicine, Section of Cardiovascular Medicine, Room H6/354 CSC (3248), University of Wisconsin Hospitals and Clinics, 600 Highland Avenue, Madison, WI 53792, USA

* Corresponding author. Tel.: +1-608-262-5291; fax: +1-608-263-0405 ctj{at}medicine.wisc.edu

Received 4 March 2002; accepted 17 April 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: The antimalarial drug halofantrine has been associated with QT interval prolongation and with fatal and nonfatal arrhythmias in patients without known underlying cardiac abnormalities. A common target for QT interval-prolonging drugs is the human ether-a-go-go gene (HERG) which encodes the pore forming subunit of the rapidly activating delayed rectifier K+ current (IKr). Methods: We studied the effects of halofantrine (0.1–1000 nM) and its major metabolite N-desbutylhalofantrine (3–1000 nM) on wild type HERG K+ channels stably expressed in HEK 293 cells, using the whole cell patch-clamp recording technique. Results: Halofantrine and N-desbutylhalofantrine blocked HERG K+ channels in a concentration-dependent manner with a half-maximal inhibitory concentration of 21.6 nM (n = 31 cells) and 71.7 nM (n = 18 cells), respectively. The development of drug block for both halofantrine and N-desbutylhalofantrine required channel activation indicative of open and/or inactivated state block. Drug washout or cell hyperpolarization resulted in minimal current recovery consistent with virtually irreversible binding. Using a ventricular action potential voltage clamp protocol, halofantrine and N-desbutylhalofantrine block of HERG current was greatest during phases 2 and 3 of the action potential waveform. Conclusion: We conclude that both halofantrine and N-desbutylhalofantrine cause high affinity block of HERG K+ channels. Although N-desbutylhalofantrine has been suggested to be a safer antimalarial agent compared to halofantrine, our results suggest that the gain in the safety margin for QT interval prolongation-related cardiotoxicity is minimal.

KEYWORDS Arrhythmia (mechanisms); Ion channels; Long QT syndrome; Sudden death


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Malaria is arguably the most important transmitted parasitic disease in humans and is endemic in over 100 countries. On an average, more than 100 million patients contract malaria each year [1] and estimates of malaria-related mortality vary from 1.5 to 2.7 million people worldwide annually [2]. Despite therapeutic progress, the drug armamentarium used to treat malaria is limited.

Halofantrine is a widely used phenanthrene-methanol class antimalarial drug that is widely prescribed in developing countries for the treatment of uncomplicated chloroquine-resistant Plasmodium falciparum malaria. It is also prescribed for travelers to malaria endemic areas to treat failed chemoprophylaxis [3–5]. Orally administered as a racemic mixture, halofantrine undergoes N-debutylation in the liver by cytochrome P450 3A4 (CYP 3A4) to its major metabolite N-desbutylhalofantrine. This metabolite is found in serum soon after administration of halofantrine usually in lower concentrations [6,7]. Both compounds are thought to contribute to the antimalarial activity of the parent drug.

Halofantrine is associated with lengthening of the QT interval in patients without known cardiac abnormalities [1,8–10]. The drug has been associated with palpitations, syncope, and fatal or near fatal arrhythmias [7,11,12]. This resulted in prescribing information for halofantrine that recommends its use only in persons who have a normal electrocardiogram, which makes its use in many less developed countries not practical [5,13]. Animal studies have confirmed that halofantrine prolongs the rate-corrected QT (QTc) interval in a concentration-dependent manner [14]. Little is known about the electrophysiological effects of N-desbutylhalofantrine.

Cardiac delayed rectifier K+ current is composed of two distinct components, the rapidly (IKr) and slowly (IKs) activating currents [15]. The IKr channel pore-forming protein is encoded by the human ether-a go-go related gene (HERG) [15–17]. Suppression of IKr causes action potential and QT interval prolongation leading to the generation of early afterdepolarizations and ventricular arrhythmias [18]. HERG channels have unique pharmacological properties and are blocked by many classes of cardiovascular and non-cardiovascular drugs that cause drug-induced long QT syndrome (for discussion, see Refs. [18–20]). In the present report, we examined the effects of halofantrine and N-desbutylhalofantrine on HERG channels heterologously expressed in a human cell line to compare their respective HERG block properties. A preliminary report of this work has appeared [21].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 DNA constructs and stable transfection of HEK 293 cells
The stable transfection and culture of human embryonic kidney (HEK) 293 cells with HERG cDNA has been previously described [22–24]. The cells were harvested from the culture dish by trypsinization, washed twice with standard MEM, and stored in this medium at room temperature for electrophysiological study on the same day.

2.2 Patch clamp recording method
Membrane currents were recorded in the whole-cell patch clamp configuration [22–24] using an Axopatch 200B amplifier. Patch electrodes typically had resistances of 3–5 M{Omega} when filled with internal pipette solution. Capacitance compensation was used in all experiments. Computer software (pCLAMP 6.02 or 8, Axon Instruments) was used to generate voltage clamp protocols, acquire data, and analyze current signals. Cells were superfused with Tyrode solution containing (in mM) 137.0 NaCl, 4.0 KCl, 1.8 CaCl2, 1.0 MgCl2, 10.0 glucose, and 10.0 HEPES/NaOH, with a pH of 7.4. The internal pipette solution contained (in mM) 130.0 KCl, 1.0 MgCl2, 5.0 EGTA, 5.0 MgATP, 10.0 HEPES/KOH, with a pH of 7.2. Solution exchanges in the cell bath were completed within 1 min. Experiments were performed at 23±1 °C except for cardiac action potential waveform clamp experiments that were performed at 35±1 °C.

2.3 Drugs and chemicals
Halofantrine (Halafan®) and N-desbutylhalofantrine were kindly provided by SmithKline Beecham, UK. The drugs were dissolved in 100% ethanol to make 10 mM stock solutions. Fresh drug aliquots were prepared on the day of the experiments by diluting stock solution with Tyrode solution. Ethanol, at a concentration of 0.01%, equivalent to the highest drug dilution studied had no effect on HERG current (data not shown).

2.4 Curve fitting and statistical methods
Data are given as a mean±standard error of the mean. Concentration-dependent effects were fit to the Hill equation (Idrug/Icontrol=1/[1+(D/IC50)nH]), where D is the drug concentration, IC50 is the drug concentration for 50% of maximal block, and nH is the Hill coefficient. Statistical significance was analyzed using a Student t-test. A P value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Halofantrine and N-desbutylhalofantrine block HERG K+ channels
Fig. 1 shows the effect of halofantrine (left panels) and N-desbutylhalofantrine (right panels) on HERG K+ current. The voltage protocol is shown in the upper traces in Fig. 1A and C. Depolarizing steps were applied from a holding potential of –80 mV to between –70 and 60 mV for 4 s, followed by a step to –50 mV for 5.7 s to elicit tail current. This pulse protocol was applied at 15-s intervals. Representative HERG current traces for control conditions and following drug exposure (30 nM halofantrine and 300 nM N-desbutylhalofantrine) to produce steady-state block are shown beneath the voltage protocols. Both drugs reduced HERG current amplitude. Fig. 1B and D shows averaged current–voltage relations obtained for HERG current measured at the end of the depolarizing step (Istep) and for peak tail current amplitude (Itail) measured following the step to –50 mV. For control conditions, HERG current activated at voltages positive to –50 to –40 mV, maximum current was reached for steps to ~10 mV, and at more positive voltages inward rectification was present because of voltage-dependent rapid inactivation [25,26]. The peak tail current was maximal after voltage steps positive to 20 mV. The current–voltage plots after drug exposure show that 30 nM halofantrine (n = 4 cells) and 300 nM N-desbutylhalofantrine (n = 4 cells) suppressed HERG current.


Figure 1
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  		Fig. 1 Effect of halofantrine and N-desbutylhalofantrine on HERG channel current. (A) and (C) show the voltage protocol and representative current traces for control (ctrl) conditions and with steady-state block by halofantrine (30 nM) and N-desbutylhalofantrine (300 nM). (B) and (D) showed averaged current–voltage relations for these conditions. See text for details.

 
The concentration-dependence of block of HERG current by halofantrine and N-desbutylhalofantrine is shown in Fig. 2A and B, respectively. The voltage clamp protocol used an initial depolarizing step to 20 mV for 4 s followed by a step to –50 mV for 5.7 s to elicit tail current, with the pulse protocol applied at 15-s intervals. The insets in Fig. 2A and B show representative current records. After obtaining the control current traces, each cell was held at –80 mV for 10 min to maintain channels in the closed state while drug was washed into the chamber. Following this the voltage clamp protocol was applied at 15-s intervals. With application of the first depolarizing step to 20 mV, HERG current amplitude initially was only minimally reduced for both halofantrine and N-desbutylhalofantrine, but decreased further during the step as additional block developed. Block of HERG current during the voltage clamp protocol reached a steady-state by the application of the fourth pulse in the sequence. These findings demonstrate that the development of high-affinity drug block required the activation of HERG channels from the closed state. Using this protocol to obtain steady-state block, halofantrine was studied at 0.1, 0.3, 3, 10, 30, 100, 300 and 1000 nM concentrations with each cell (n = 31) exposed to only one drug concentration. N-Desbutylhalofantrine was studied at 3, 10, 30, 100, 300 and 1000 nM concentrations with each cell (n = 18) also exposed to only one drug concentration. For halofantrine, the IC50 value for steady-state peak tail current block was 21.6±3.6 nM with a Hill coefficient of 0.62, and for N-desbutylhalofantrine the IC50 value was slightly higher at 71.7±7.3 nM with a Hill coefficient of 1.36.


Figure 2
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  		Fig. 2 Concentration-dependence of block of HERG tail current peak amplitude. (A) Shows the effect of halofantrine and (B) shows the effect of N-desbutylhalofantrine. Number of cells studied at each drug concentration is given in parentheses. Data for each drug were fit with the Hill equation. Insets reproduce five example current records showing the development of block with 1 µM of drug, respectively. The labeled current traces are for the control, and the 1st (1) and 4th (4) depolarizing pulses following drug wash-in and show use-dependent drug block.

 
3.2 Halofantrine and N-desbutylhalofantrine unblock minimally from HERG channels during repolarization
Recovery from drug block of HERG channels is highly variable. For drugs such as methanesulfonanilide antiarrhythmic compounds (e.g. E-4031, MK-499 and dofetilide) unbinding occurs very slowly so that drug block is essentially irreversible. This has been attributed to trapping of charged drug moiety within the inner vestibule of the pore [19,20]. In contrast, other drugs (e.g. verapamil, cocaine) have been shown to rapidly unblock following membrane repolarization possibly due to equilibrium diffusion of the uncharged drug moiety [24] or to the direct escape of charged drug moiety via the open channel [27]. To assess voltage-dependent unbinding of halofantrine and N-desbutylhalofantrine, a two-pulse protocol was used. The voltage clamp protocol is shown in Fig. 3A. From a holding potential of –80 mV, a 100-ms-long step to 60 mV was applied to rapidly activate HERG current followed by a 10-s-long step to 0 mV to obtain a steady level of drug block. The cell membrane was repolarized to –80 mV for a variable period of time before a test pulse sequence to 60 mV for 100 ms and then to 0 mV for 200 ms was applied to assess the amount of HERG current that could be elicited following repolarization. Halofantrine (100 nM) or N-desbutylhalofantrine (300 nM), drug concentrations that cause similar levels of block, was continuously perfused in the chamber while the two-pulse protocol was applied at 60-s intervals. Fig. 3B (halofantrine) and 3C (N-desbutylhalofantrine) show example HERG current records. Halofantrine or N-desbutylhalofantrine was added to the chamber while each cell was held at –80 mV. The first depolarizing pulse sequence (1st step) resulted in a large amplitude HERG current that decreased during the 10-s-long step as drug block developed, and steady-state block was reached by the second application of the two-pulse protocol. Recovery intervals of up to 50 s resulted in virtually no increase in HERG current amplitude consistent with nearly irreversible drug binding to HERG channels by both halofantrine (n = 3 cells) and N-desbutylhalofantrine (n = 4 cells). In other experiments, washout for 5 min of 100 nM halofantrine (n = 5 cells) or 300 nM N-desbutylhalofantrine (n = 3 cells) did not result in recovery of HERG current (data not shown), consistent with essentially irreversible drug binding.


Figure 3
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  		Fig. 3 Recovery of HERG current during repolarization. (A) Shows the voltage protocol. The recovery interval ({Delta}Time) between the conditioning and test pulses was varied from 100 ms and 50 s. (B) and (C) show representative currents. Virtually no recovery of HERG current during perfusion with halofantrine (100 nM, B) or N-desbutylhalofantrine (300 nM, C) for recovery intervals up to 50 s. See text for discussion.

 
3.3 Cardiac action potential clamp
To examine the effects of halofantrine and N-desbutylhalofantrine on HERG current, a ventricular action potential clamp method was used as shown in Fig. 4A. At positive voltages reached during action potential depolarization, HERG channels rapidly inactivate, causing the control HERG current amplitude to initially be small. During action potential repolarization, HERG channels recover from inactivation to rapidly reopen and then to more slowly deactivate, which increases their occupancy in the open state and the amplitude of HERG current. With terminal repolarization HERG current then deactivates. This is shown in the control records in Fig. 4B and C where HERG current reaches its maximum during phases 2 and 3 of the action potential clamp waveform. Halofantrine (100 nM, Fig. 4B) or N-desbutylhalofantrine (1 µM, Fig. 4C) was then superfused for 10 min and the action potential clamp protocol was applied at 5-s intervals to obtain a steady-state of drug block. HERG current was suppressed throughout the action potential clamp waveform with the reduction most evident during phases 2 and 3. Similar findings were obtained in three cells with each drug. For each cell, the peak outward HERG current amplitude during phases 2 and 3 of the action potential clamp waveform was measured for the control current and this value was compared to the current remaining at the same time point following drug exposure. For 100 nM halofantrine, HERG current amplitude was reduced by 71.4±3.6% (P<0.05), and for 1 µM N-desbutylhalofantrine HERG current amplitude was reduced by 94.7±1.5% (P<0.05). These reductions of HERG current amplitude are nearly identical to the reductions of HERG current amplitude obtained using conventional voltage clamp square pulse protocols (see Fig. 2A and B). The reduction in HERG current provides a mechanism for action potential prolongation.


Figure 4
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  		Fig. 4 Ventricular action potential clamp. The action potential clamp waveform is shown in (A) (holding potential –80 mV). Representative HERG current traces for control conditions and steady-state drug block are shown for halofantrine (B) and N-desbutylhalofantrine (C).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Halofantrine-induced prolongation of the QT and QTc intervals on an electrocardiogram was initially reported in patients with uncomplicated falciparum malaria receiving halofantrine at recommended doses [28,29]. At a drug dose of 72 mg/kg (threefold higher than the recommended dose) halofantrine caused dose-dependent lengthening of QTc intervals in 61 patients with multidrug-resistant falciparum malaria [6]. These investigators suggested that QT interval prolongation was associated with the parent drug halofantrine, but not its major metabolite N-desbutylhalofantrine [29]. Subsequent studies have yielded conflicting results. Matson et al. reported that halofantrine and N-desbutylhalofantrine both could cause QT interval lengthening [30]. In a different study the sum of the halofantrine and N-desbutylhalofantrine serum concentrations correlated with QT interval lengthening, although the relative effects were not determined [8]. In a brief report correlating serum drug levels and adverse cardiac events, Gundersen et al. reported halofantrine-associated ventricular fibrillation in a patient without predisposing QTc prolongation [7]. They found that the serum level for N-desbutylhalofantrine (324 µg/l) exceeded the serum level for halofantrine (53 µg/l) and suggested a key role for the metabolite in the cardiotoxicity of halofantrine. Limited data exist that directly compare halofantrine and N-desbutylhalofantrine. In feline ventricular myocytes and perfused hearts, Wesche et al. showed that halofantrine was slightly more potent at suppressing IKr and prolonging the QT interval than was N-desbutylhalofantrine [31].

Our findings provide evidence that closed state block by halofantrine and N-desbutylhalofantrine is minimal, rather, our findings suggest that both drugs block preferentially the activated (e.g. open and/or inactivated) states of HERG channels. The experiments, however, do not distinguish between open or inactivated state block. This agrees with many previous reports of other drugs that block HERG channels in a similar manner, and with previous findings with halofantrine by Tie et al. [32]. Our results also suggest that both halofantrine and N-desbutylhalofantrine bind to HERG channels to cause essentially irreversible block. The mechanism of irreversible block has been suggested to involve drug binding within the inner vestibule of the pore region to aromatic amino acid residues of the HERG protein [19,20].

The present work is the first report comparing these drugs on a cloned human ion channel. Our work provides new information about potential cardiac toxicity of the anti-malarial drug halofantrine. The principal finding is that both halofantrine and its metabolite, N-desbutylhalofantrine, cause high affinity block of HERG K+ channels. The IC50 values, while not identical (21.6 and 71.7 nM, respectively, P<0.05) suggest that these drugs block HERG channels with relatively similar affinities. The value we found for halofantrine-induced block of HERG channels is close to the IC50 value (196.9 nM) recently reported for HERG channels expressed in CHO cells [32], however, these investigators did not study N-desbutylhalofantrine. The metabolite, in part because of its slower elimination kinetics, can achieve higher steady-state plasma concentrations than the parent compound [7]. Our data indicate that halofantrine and N-desbutylhalofantrine are among the more potent HERG channel blocking drugs reported, and suggest that drug screening in heterologous expression systems may have clinical utility. Block of HERG current, or IKr in native heart cells, is well known to cause drug-induced long QT syndrome. This occurs with several antiarrhythmic drugs, as well as with many other classes of drugs including macrolide antibiotics [33], fluoroquinolone antibiotics [34,35], antipsychotics [36], antihistamines [37,38], and gastrointestinal prokinetic agents [22].

The role of drug metabolites in drug-induced long QT syndrome is both complex and important. A role for drug metabolites in cardiotoxicity is being increasingly recognized by the pharmaceutical industry [39]. For some drugs such as astemizole, its principal metabolite (desmethylastemizole) is known to cause block of HERG channels that is equipotent to the parent compound, and under some conditions it is the metabolite that has been postulated to be the principal cause of drug-induced long QT syndrome [38]. For astemizole, it is known to have additional metabolites (norastemizole or tecastemizole) that also exert HERG channel block [38]. For other drugs such as terfenadine, its principal metabolite (terfenadine carboxylate or fexofenadine) exerts only very weak block of HERG channels, and it has become a clinically important antihistamine drug thought not to cause long QT syndrome [40]. N-Desbutylhalofantrine has been suggested to be a potentially safer antimalarial drug compared to its parent compound [31]. Our results do not provide a conclusive answer to this question. However, the finding that the IC50 values for HERG channel block are similar suggests that improvement in the safety margin for QT interval prolongation-related cardiotoxicity is likely to be minimal.

Time for primary review 15 days.


   Acknowledgements
 
Supported in part by NIH R01 HL60723. S.R. is supported by a postdoctoral fellowship grant from the American Heart Association, Northland Affiliate. The authors thank Corey L. Anderson for his expert technical assistance with cell culture.


   Notes
 
1 Authors contributed equally and should be considered co-first authors. Back


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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D. A. Smith and R. S. Obach
SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING
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