Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats

Abstract

Background and purpose: Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.

Experimental approach: Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4-40 mg·kg(-1)·d(-1)) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.

Key results: In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.

Conclusions and implications: The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.

Figure 1

The mean ± SD concentrations of halofantrine (HF) and desbutylhalofantrine (DHF) enantiomers in normolipidaemic (NL) and hyperlipidaemic (HL) rats 12 h after the last (+/−)-HF doses of 4, 10, 20, 30 and 40 mg·kg⁻¹·d⁻¹.

Figure 2

The correlation between plasma and heart concentration of halofantrine (HF) enantiomers with corresponding desbutylhalofantrine (DHF) enantiomers in normolipidaemic (NL) and hyperlipidaemic (HL) rats following administration of 4, 10, 20, 30 and 40 mg·kg⁻¹·d⁻¹.

Figure 3

The correlation between heart and total or unbound plasma concentration of halofantrine (HF) enantiomers in normolipidaemic (NL) and hyperlipidaemic (HL) rats following administration of 4, 10, 20, 30 and 40 mg·kg⁻¹·d⁻¹.

Figure 4

The correlation between QT intervals and plasma or heart concentration of halofantrine enantiomers in normolipidaemic (NL) and hyperlipidaemic (HL) rats given 4, 10, 20, 30 and 40 mg·kg⁻¹·d⁻¹.