کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2486197 | 1114377 | 2011 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Effect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
Hyperlipidemia (HL) was previously shown to lower liver uptake of the more potent (â) 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 (5Â mg/kg) with or without a single oral dose of racemic KTZ (40Â mg/kg). Serial blood samples were collected over 8Â 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 MDZâunbound 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 âassociated 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. © 2011 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 100:4986-4992, 2011
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 100, Issue 11, November 2011, Pages 4986-4992
Journal: Journal of Pharmaceutical Sciences - Volume 100, Issue 11, November 2011, Pages 4986-4992
نویسندگان
Dalia A. Hamdy, Dion R. Brocks,