Effect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat.

Abstract:

:Hyperlipidemia (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.

journal_name

J Pharm Sci

authors

Hamdy DA,Brocks DR

doi

10.1002/jps.22675

subject

Has Abstract

pub_date

2011-11-01 00:00:00

pages

4986-92

issue

11

eissn

0022-3549

issn

1520-6017

pii

S0022-3549(15)31855-4

journal_volume

100

pub_type

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