title: Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
abstract: The adrenal gland is the most common toxicological target in the endocrine system, and inhibition of adrenal steroidogenesis by drugs can be fatal in humans. However, methods to evaluate the drug effect are limited. Recently, simultaneous measurement of multiple steroids, including precursors, has become possible. Here, we evaluated the usefulness of this simultaneous measurement for the evaluation of drug effects on adrenal steroidogenesis in vivo. For this purpose, we measured plasma concentrations of adrenal steroids in rats dosed with ketoconazole, a known inhibitor of adrenal steroidogenesis, and examined its relationship with the changes in histopathology and mRNA expression of steroidogenic enzymes in the adrenal gland. Ketoconazole (150mg/kg/day) was orally administered to male rats for 7 days. The adrenal weight was high, and the zona fasciculata/reticularis were hypertrophic with an accumulation of lipid droplets. mRNA expression of CYP11A1, a rate-limiting enzyme in adrenal steroidogenesis, was slightly high in the adrenal gland. Plasma concentration of deoxycorticosterone was markedly high, while there were no significant changes in that of corticosterone, progesterone, or pregnenolone. The changes in the adrenal gland and plasma concentration of steroids were thought to reflect inhibited metabolism of deoxycorticosterone to corticosterone through inhibition of CYP11B1, and compensatory reaction for the inhibition. The compensatory reaction was thought to have masked decrease of corticosterone. These results suggest that simultaneous measurement of multiple steroids can enable sensitive evaluation of drug effects on adrenal steroidogenesis in vivo, while providing insight into the underlying mechanism of the effect.
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: tomoaki-tochitani@ds-pharma.co.jp.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tochitani
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Kouchi
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Izuru
authors.initials: I
authors.lastname: Miyawaki
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Funabashi
mesh_terms: D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D003345:Corticosterone / Q000097:blood*; D003900:Desoxycorticosterone / Q000097:blood*; D007654:Ketoconazole / Q000008:administration & dosage / Q000633:toxicity*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley
chemical_list: D019394:Ki-67 Antigen; D003900:Desoxycorticosterone; D002786:Cholesterol Side-Chain Cleavage Enzyme; D007654:Ketoconazole; D003345:Corticosterone
keywords: Adrenal steroidogenesis; Drug; In vivo; Ketoconazole; Rat; Simultaneous measurement of multiple steroids