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AuthorHamdy, D. A.
AuthorBrocks, D. R.
Available date2015-11-05T13:23:45Z
Publication Date2011
Publication NameJournal of Pharmaceutical Sciences
ResourceWiley Online Library
CitationHamdy, D. A. and Brocks, D. R. (2011), Effect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat. Journal of Pharmaceutical Sciences, 100: 4986-4992.
ISSN1520-6017
URIhttp://dx.doi.org/10.1002/jps.22675
URIhttp://hdl.handle.net/10576/3744
AbstractHyperlipidemia (HL) was previously shown to lower liver uptake of the more potent (-) enantiomer of ketoconazole (KTZ) in rat. The current study examined the possible modifying influence of experimental HL on a KTZ pharmacokinetic interaction with midazolam (MDZ). Normolipidemic and hyperlipidemic rats were administered a single intravenous dose of MDZ (5 mg/kg) with or without a single oral dose of racemic KTZ (40 mg/kg). Serial blood samples were collected over 8?h following MDZ injections via jugular vein cannulas. Plasma was jointly assayed for MDZ and KTZ concentrations using a validated assay. MDZ mean clearance (CL) was unchanged by KTZ coadministration. HL caused a significantly 61% lower MDZ-unbound fraction and decreases in volume of distribution (VD) but by itself had no effect on MDZ CL. This suggested that MDZ could bind to lipoproteins. With KTZ coadministered to hyperlipidemic rats, there were significant decreases in MDZ CL and VD. HL caused a decrease in unbound plasma fraction of oral KTZ but no significant difference in its pharmacokinetics. HL caused a more pronounced KTZ -associated inhibition of MDZ CL. This may be related to the decrease of MDZ's unbound fraction and perhaps to attenuation of CYP3A by HL in the rat.
Languageen
PublisherJohn Wiley & Sons, Ltd.
Subjectprotein binding
CYP3A
pharmacokinetics
pharmacodynamics
enzyme inhibition
antifungal drugs
TitleEffect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat
TypeArticle
Issue Number11
Volume Number100
dc.accessType Abstract Only


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