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.
Brocks
Dion R
DR
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada. dbrocks@pharmacy.ualberta.ca
Wasan
Kishor M
KM
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