The Influence of Lipids on Stereoselective Pharmacokinetics of Halofantrine: Important Implications in Food‐Effect Studies Involving Drugs That Bind to Lipoproteins

Brocks, Dion R.; Wasan, Kishor M.

doi:10.1002/jps.10182

Cited by 50 publications

(65 citation statements)

References 23 publications

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“…This being the case, any factor that increases plasma lipoprotein concentrations, such as ingestion of a high fat meal, or familial hyperlipoproteinemia, might be expected to give rise to reduced fu in blood or plasma, reduced CL, and higher blood or plasma concentrations. Indeed, this has been observed for other lipoprotein-binding drugs, such as halofantrine and amiodarone, in dogs [2] and rats [3,4] given a high-fat content meal.…”

Section: Introductionmentioning

confidence: 84%

The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

Brocks

Ala

Aliabadi

2005

Biopharm & Drug Disp

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The response of cyclosporine A (CyA) blood concentrations following changes in lipoprotein levels have been inconsistent. Some studies show increases in concentrations, whereas others have shown decreases. The intent of this study was to examine the effect of two rat models of increased lipoprotein on the pharmacokinetics of CyA. One was a simulated high fat content meal, in which 1% cholesterol in peanut oil was administered. The other was the poloxamer 407-induced model of hyperlipidemia. Rats in these two groups were compared to a group fasted overnight before the study. In rats given a simulated high fat meal, at most time points the mean blood and plasma concentrations were lower, though not significantly, compared to fasted animals. Oral lipid led to no significant changes in the measured pharmacokinetic parameters of blood or plasma area under the concentration vs time curve (AUC), clearance (CL), volume of distribution (Vd) or plasma unbound fraction. In the poloxamer 407-treated hyperlipidemic rats there were significant reductions in plasma unbound fraction plasma, Vd and terminal half-life, but not AUC or CL, compared to normolipidemic rats. In contrast, the CL, Vd and t1/2 in the oral lipid-fed rats were all significantly higher than the poloxamer 407 treated animals. Oral absolute bioavailability of CyA was unchanged by oral lipid. In humans and rats the pharmacokinetics of CyA in the face of increased lipoprotein levels do not correspond well to what is typically seen for other drugs that are known to bind to lipoproteins.

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Section: Introductionmentioning

confidence: 84%

The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

Brocks

Ala

Aliabadi

2005

Biopharm & Drug Disp

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“…To test the applicability of the developed method, three Wistar rats were each orally administered with 7 mg/kg of Hf HCl in dispersed systems containing unsaturated fatty acids in rats has been shown to increase the bioavailability of Hf (Holm et al, 2001;Brock and Wasan, 2002). Therefore, this work was designed with olive oil as a lipid vehicle.…”

Section: Assay Of Hf In Ratmentioning

confidence: 99%

Determination of halofantrine and its main metabolite desbutylhalofantrine in rat plasma by high‐performance liquid chromatography with on‐line UV irradiation and peroxyoxalate chemiluminescence detection

Amponsaa-Karikari

Kishikawa

Ohyama

et al. 2008

Biomedical Chromatography

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A sensitive, selective and reliable method has been developed and validated for the determination of halofantrine and its metabolite desbutylhalofantrine in rat plasma using 9,10-diphenylanthracene as an internal standard. The method is based on peroxyoxalate chemiluminescence detection of hydrogen peroxide produced from fused aromatic rings in the structures of halofantrine and desbutylhalofantrine upon UV irradiation. Using spiked rat plasma, good linear relationships were obtained for both halofantrine and desbutylhalofantrine between peak height ratios (vs internal standard) and their corresponding concentrations over a range of 0.01-0.8 microg/mL with correlation coefficients of at least 0.997. The detection limits at signal-to-noise ratio of 3 using 0.2 mL of rat plasma were 1.5 and 1.4 ng/mL for halofantrine and desbutylhalofantrine, respectively. Relative standard deviations (n = 3) intra- and inter-day were between 0.5 and 5.4% for all the studied concentrations. Using this method with simple sample treatment, halofantrine and desbutylhalofantrine in rat plasma could be precisely determined without interference from endogenous substances. The method was successfully applied to the measurement of the time courses of plasma halofantrine concentration after oral administration of the drug (7 mg/kg) to rats.

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“…stereoselectivity, 5,11 ratio of HF to DHF plasma concentration ratio, 10 and plasma concentration responses to factors such as effect of a high fat meal on oral bioavailability. 15,16 Rat has been used as a model for study of HF lymphatic transport and for the effect of hyperlipidemia on its pharmacokinetics. 15,17 With respect to the metabolism of HF, although it is known that (À)-HF is preferentially metabolized by rat liver homogenates, 18 to date, little is known of the enzymes involved in the formation of equipotent DHF in the rat.…”

Section: Introductionmentioning

confidence: 99%

The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: Evidence of tissue‐specific enantioselectivity in microsomal metabolism

et al. 2006

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The pharmacokinetics of the antimalarial drug (+/-)-halofantrine are stereoselective in humans and rats. To better understand the stereoselective metabolism of the drug to its primary metabolite, desbutylhalofantrine (DHF), a series of in vitro and in vivo experiments were undertaken in the rat. Formation of (-)-DHF exceeded that of (+)-DHF in liver microsomes [(-):(+) ratio of intrinsic formation clearances = 1.4]. In contrast, in intestinal microsomes no significant stereoselectivity was noted in the formation of the DHF enantiomers. Intestinal microsomes were also less efficient at producing the DHF enantiomers than were liver microsomes. Based on kinetic analysis of the DHF formation, there appeared to be more than one enzyme involved in the biotransformation. (+/-)-Ketoconazole (KTZ) effectively inhibited the formation of both DHF enantiomers by both liver and intestinal microsomes, although the reduction was more marked in liver microsomes. Through a combination of the use of CYP antibodies and recombinant CYP isoenzymes, the involvement of CYP 2B1/2, 3A1, 3A2, 1A1, 2C11, 2C6, 2D1, and 2D2 were implicated in the metabolism of halofantrine to DHF. Of these, CYP3A1/2 and CYP2C11 appeared to be the primary isoenzymes involved, although CYP2C11 showed greater (+)-DHF than (-)-DHF formation, whereas for CYP3A1 it was similar to the isolated rat liver microsomes. In vivo, oral (+/-)-KTZ caused significant increases in plasma halofantrine and decreases in DHF enantiomer plasma concentrations.

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The Influence of Lipids on Stereoselective Pharmacokinetics of Halofantrine: Important Implications in Food‐Effect Studies Involving Drugs That Bind to Lipoproteins

Cited by 50 publications

References 23 publications

The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

Determination of halofantrine and its main metabolite desbutylhalofantrine in rat plasma by high‐performance liquid chromatography with on‐line UV irradiation and peroxyoxalate chemiluminescence detection

The stereoselective metabolism of halofantrine to desbutylhalofantrine in the rat: Evidence of tissue‐specific enantioselectivity in microsomal metabolism

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