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Tissue Accumulation Kinetics of Ciclesonide‐active Metabolite and Budesonide in Mice
Author(s) -
Mårs Ulla,
d'Argy Roland,
Hallbeck Karin,
MillerLarsson Anna,
Edsbäcker Staffan
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12043
Subject(s) - metabolite , ciclesonide , budesonide , active metabolite , pharmacokinetics , dosing , chemistry , pharmacology , distribution (mathematics) , medicine , endocrinology , corticosteroid , asthma , mathematical analysis , mathematics , inhaled corticosteroids
Inhaled corticosteroids ( ICS ) are mainstay treatment of asthma and chronic obstructive pulmonary disease. However, highly lipophilic ICS accumulate in systemic tissues, which may lead to adverse systemic effects. The accumulation of a new, highly lipophilic ICS , ciclesonide and its active metabolite (des‐ CIC ) has not yet been reported. Here, we have compared tissue accumulation of des‐ CIC and an ICS of a moderate lipophilicity, budesonide ( BUD ), after 14 days of once‐daily treatment in mice. Single, three or 14 daily doses of [ 3 H ]‐des‐ CIC or [ 3 H ]‐ BUD were administered subcutaneously to male CD 1 albino mice, which were killed at 4 hr, 24 hr or 5 days after the last dose. Distribution of tissue concentration of radioactivity was studied by quantitative whole‐body autoradiography. Pattern of radioactivity distribution across most tissues was similar for both corticosteroids after a single as well as after repeated dosing. However, tissue concentration of radioactivity differed between des‐ CIC and BUD . After a single dose, concentrations of radioactivity for both corticosteroids were low for most tissues but increased over 14 days of daily dosing. The tissue radioactivity of des‐ CIC at 24 hr and 5 days after the 14th dose was 2–3 times higher than that of BUD in majority of tissues. Tissue accumulation, assessed as concentration of tissue radioactivity 5 days after the 14th versus 3rd dose, showed an average ratio of 5.2 for des‐ CIC and 2.7 for BUD ( p < 0.0001). In conclusion, des‐ CIC accumulated significantly more than BUD . Systemic accumulation may lead to increased risk of adverse systemic side effects during long‐term therapy.