The influence of lipids on stereoselective pharmacokinetics of halofantrine: Important implications in food-effect studies involving drugs that bind to lipoproteins.
The objective of this study was to determine the effect of lipids on the pharmacokinetics of halofantrine enantiomers. Rats were given (+/-)-halofantrine HCl 2 mg/kg i.v., or 7 mg/kg orally. Some rats were rendered hyperlipidemic by intraperitoneal administration of poloxamer 407 1 g/kg, followed by (+/-)-halofantrine HCl intravenously. In other normolipidemic rats, (+/-)-halofantrine was administered under fasted conditions, or after peanut oil given orally. Halofantrine enantiomer plasma concentrations were considerably (>10-fold) increased in hyperlipidemia. Decreases were noted in the clearance, volume of distribution and the unbound fraction in plasma of the hyperlipidemic rats. Peanut oil caused a significant 28% reduction in clearance of the (-), but not the (+) enantiomer (mean clearance reduced 11%) of halofantrine. After oral halofantrine, peanut oil resulted in a two- to threefold increase in the plasma area under the curves of halofantrine enantiomers. Halofantrine enantiomer pharmacokinetics are highly dependent upon plasma lipid concentrations. Oral lipids may result in a stereoselective interaction at the level of clearance. Because lipids may affect clearance of drugs that bind to lipoproteins, in determining bioavailability of such drugs in food-effect studies, reference intravenous groups should be included to separate true increase in bioavailability from the effects of decreased clearance.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada. dbrocks@pharmacy.ualberta.ca
Dion R
DR
Brocks
Kishor M
KM
Wasan
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000494:pharmacology; D018565:Food-Drug Interactions; D006949:Hyperlipidemias / Q000378:metabolism; D007275:Injections, Intravenous; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D000074241:Peanut Oil; D010616:Phenanthrenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010938:Plant Oils / Q000494:pharmacology; D020442:Poloxamer / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014280:Triglycerides / Q000097:blood
D000962:Antimalarials; D001798:Blood Proteins; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D000074241:Peanut Oil; D010616:Phenanthrenes; D010938:Plant Oils; D014280:Triglycerides; D020442:Poloxamer; D002784:Cholesterol; C023768:halofantrine