Effects of Simvastatin on Alveolar Regeneration and Its Relationship to Exposure in Mice with Dexamethasone-Induced Emphysema

• Published in: Biological & pharmaceutical bulletin 2017/02/01, Vol.40(2), pp.155-160
• Main Authors: Hirooka, Shihomi, Ueno, Misaki, Fukuda, Satoko, Miyajima, Atsushi, Hirota, Takashi
• Format: Article
• Language: English
• Subjects: Acids; alveolar regeneration; Alveoli; Animals; Dexamethasone; Dexamethasone - toxicity; Dose-Response Relationship, Drug; Emphysema; Exposure; Female; Male; Mice; Mice, Inbred ICR; mouse; Oral administration; pharmacokinetics; Pregnancy; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - pathology; Pulmonary Alveoli - physiology; Pulmonary Emphysema - chemically induced; Pulmonary Emphysema - drug therapy; Pulmonary Emphysema - pathology; Regeneration - drug effects; Regeneration - physiology; Rodents; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Steroids; Treatment Outcome
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b16-00637

In the present study, the relationship between systemic exposure of simvastatin (SV) hydroxy acid (SV-acid), an active form of SV, and its alveolar regeneration rates was investigated using emphysema model mice created by postnatal treatment of dexamethasone. In a model with young animals, the mice were treated with SV for 10 d from postnatal day 42. Similar alveolar regeneration with a % mean linear intercept (Lm) recovery of 60 to 70% by histochemical observation was observed in mice after intraperitoneal administration at dose in the range of 4–100 µg/mouse. The % Lm recovery after oral administration of 20 µg/mouse was comparable with that after intraperitoneal administration at a dose of 4 µg/mouse, when their exposure of SV-acid was almost similar in both treated groups. Regardless of the route of administration, the recovery can depend on the exposure level of SV-acid, and to the maximum was about 60–70%. On the other hand, in a model with adult animals, the mice were intraperitoneally administrated SV at a dose of 4 µg/mouse for 10 d from postnatal day 152. Compared to young animals, less % Lm recovery was observed in adult mice even their systemic exposures of SV-acid were similar.