Research ArticlesEffect of Oral Ketoconazole on First‐pass Effect of Nifedipine After Oral Administration in Dogs
Section snippets
INTRODUCTION
Ketoconazole (KTZ) is an oral antifungal agent with a broad spectrum of activity against systemic mycotic infections.1 This drug is well known to inhibit metabolic activity of cytochrome P‐4503A (CYP3A). There have been many reports that in in vitro experiments KTZ potently inhibits biotransformations of CYP3A substrates such as midazolam,2 terfenadine,3 cyclosporine,4 and tacrolimus.5 Other in vivo studies have shown that KTZ decreases the clearance of CYP3A substrates, tacrolimus,6
Materials
KTZ was purchased as KTZ tablet (Nizoral®) from Janssen Pharmaceutica (Titusville, NJ) and as a reagent from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). NIF was obtained as a product (Emaberin L® capsule) from Shionogi and Co., Ltd. (Osaka, Japan) and as a reagent from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Nisoldipine was a gift from Bayer AG (Leverkusen, German). All other chemicals used as reagents were of analytical and HPLC grade.
Animals
Four beagle dogs (male, 1 year old)
RESULTS
Plasma NIF concentration–time curves after intravenous administration with and without the KTZ treatment are showed in Figure 1. After KTZ pretreatment, plasma NIF concentrations increased more than fourfold. The NIF parameters after intravenous administration obtained from pharmacokinetic analysis are represented in Table 1. After KTZ pretreatment, CLtot decreased to approximately 50%, whereas t1/2β increased but not markedly (1.5‐fold). Vdss of NIF was not almost changed.
Plasma NIF
DISCUSSION
Oral KTZ treatment affected NIF pharmacokinetics, by a slower elimination of NIF without altering its volume of distribution in the body. In dogs, similar to humans, NIF was found to be eliminated mainly via metabolic pathways, because the parent drug was not detected in urine during 12 h after intravenous or oral administration in preliminary study. Therefore, the change in the disposition of NIF is mainly due to inhibition of NIF biotransformation. CLtot of NIF decreased to about 50% during
Acknowledgements
We are grateful to the Bayer AG (Leverkusen, German) for the gift of nisoldipine. We also wish to thank Dr. A.S.J.P.A.M. van Miert for helpful comments about the manuscript.
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