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spectrum.' Therefore ketoconazole is commonly used in patients with immunosuppression who are taking prednisone. Imidazole derivatives such as ...
Impact of ketoconazole on the metabolism of prednisolone The impact of ketoconazole (200 mg for 7 days) on the kinetics of oral prednisone and intravenous prednisolone and on the apparent activity of the 611-hydroxylase was investigated in 10 healthy volunteers. The ratio of urinary 613-0H-cortiso1/17-0H-corticosteroids declined by >50% and the urinary excretion of 613-0H-prednisolone decreased more than twofold in all subjects. The decline of the activity of the 613-hydroxylase was associated with impaired metabolic and renal clearances of total and unbound prednisolone. The ratios of the AUCs of prednisolone/prednisone after oral prednisone and intravenous prednisolone were independent of the administration of ketoconazole, suggesting that the enzymes responsible for the interconversion of prednisolone prednisone were not affected by ketoconazole. Thus ketoconaz,ole inhibits 613-hydroxylase and increases the exposure of the body to the biologically active unbound prednisolone after oral prednisone or intravenous prednisolone. (CLIN PHARmAcm, THER 1989;45:366-72.)

Regula M. Ziircher, MD, B. M. Frey, PhD, and F. J. Frey, MD Berne, Switzerland Ketoconazole is an oral antifungal agent with a broad spectrum.' Therefore ketoconazole is commonly used in patients with immunosuppression who are taking prednisone. Imidazole derivatives such as ketoconazole are known to inhibit the activity of some oxidases of the cytochrome P-450.2-7 Ketoconazole significantly diminishes the clearance of chlordiazepoxide yet does not affect the clearance of antipyrine or theophylline.''' Prednisolone is metabolized by mixed-function oxidases in the liver." Concomitant administration of ketoconazole with prednisone may therefore increase prednisolone concentrations and by that enhance the biologic efficacy in patients treated with prednisone. Thus the purpose of the present investigation was to assess the impact of ketoconazole therapy on the metabolism of prednisolone, extending observations made by Glynn et al.' and Kandrotas et al." about the influence of ketoconazole on the kinetics of another corticosteroid (i.e. , methylprednisolone).

MATERIAL AND METHODS Subjects. Ten healthy volunteers (five women and five men) with normal physical activity, ranging in age From the Medizinische Poliklinik and Department of Clinical Pharmacology, University of Berne. Supported by the Swiss National Foundation for Scientific Research (grant No. 3.868-0.88) and a grant from Janssen Phannaceutica, Baar, Switzerland. Received for publication April 27, 1988; accepted July 28, 1988. Reprint requests: F. J. Frey, MD, Medizinische Poliklinik, 3010 Berne-Inselspital, Switzerland.

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from 23 to 47 years and weight from 62 to 96 kg, participated in the study. Two of the subjects were moderate smokers, none used oral contraceptives, and none were on a special diet. Studies were performed after an overnight fast. During the first 5 hours of the steroid kinetics, 500 ml water at time 0 and 150 minutes was given. The steroids and ketoconazole were well tolerated by all subjects investigated. Tests of kidney and liver function were normal in all subjects. The study was approved by the ethics committee at our institution. Protocol. All subjects were given an intravenous bolus of prednisolone sodium phosphate ester corresponding to 0.8 mg/kg prednisolone (Hydeltrasol; Merck, Sharp & Dohme, Westpoint, Pa.) and an oral dose of 0.8 mg / kg prednisone on two occasions, once before and once with the administration of 200 mg ketoconazole (Janssen Pharmaceutica, Belgium) after ketoconazole had been given for 6 to 7 days. The sequence of the route of administration was the same with and without ketoconazole in each subject. On each study day when steroids were given, 10 ml blood samples were collected just before steroid administration and 5, 10, 15, 30, 60, 90, 120, 180, 300, 540, 720, and 1440 minutes after intravenous prednisolone dosing and 15, 30, 60, 120, 180, 300, 540, 720, and 1440 minutes after oral prednisone administration. Blood samples were collected in heparinized Vacutainer tubes (Pecton-Dickinson and Co., Rutherford, N.J.) and centrifuged immediately. The plasma was removed and then frozen at 30° C until assayed. On all study days,

VOLUME 45 NUMBER 4

Ketoconazole and prednisolone metabolism

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Table I. Pharmacokinetic parameters of prednisolone before and after the administration of ketoconazole

Total prednisolone Total body clearance (ml/min x kg) Renal clearance (ml/min x kg) Fractional renal clearance Nonrenal clearance (ml/min X kg) Mean residence time (mm) Volume of distribution (L/kg) Systemic availability of total prednisolone after oral prednisone Unbound prednisolone Total body clearance (tnl/min X kg) Renal clearance (ml! mm X kg) Fractional renal clearance Nonrenal clearance (ml/mM X kg) Mean residence time (min) Volume of distribution (L/kg) Systemic availability of unbound prednisolone after oral prednisone Values are the mean

After ketoconazole

p Value

2.37 ± 0.30 0.61 -± 0.16

1.72 ± 0.20 0.44 ± 0.11 0.27 ± 0.12 1.27 ± 0.15 317 -±- 40 0.53 ± 0.08 0.74 ± 0.07