Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11ß-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Inhibition of the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11ß-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects. Nonlinear, more than dose-proportional PKs were observed for ASP3662 after single-dose administration, particularly at lower doses (≤ 6 mg); the PKs at steady state were dose proportional, although the time to ASP3662 steady state was dose dependent at lower doses (≤ 2 mg). Similar PKs were observed among young Japanese, young non-Japanese, and elderly non-Japanese subjects. Specific inhibition of 11ß-HSD1 occurred after both single and multiple doses of ASP3662. A marked dissociation between PKs and PDs was observed after single but not multiple doses of ASP3662. ASP3662 was generally safe and well tolerated.

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype.

OBJECTIVE: Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. DESIGN: This was a prospective longitudinal observation study conducted over 5 years. METHODS: A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. RESULTS: Baseline higher 5α-reductase (5αR) activity, but not 11ß-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11ß-hydroxysteroid dehydrogenase type 2 activity. CONCLUSIONS: Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.

Reduced 11beta-hydroxysteroid dehydrogenase type 1 activity in obese boys.

OBJECTIVE: The incidence of childhood obesity and type 2 diabetes has reached epidemic proportions. Glucocorticoid excess causes central obesity and diabetes mellitus as seen in Cushing's syndrome. The 11beta-hydroxysteroid dehydrogenase type 1 enzyme (11beta-HSD1) regenerates active cortisol from inactive cortisone. Altered 11beta-HSD1 may cause tissue-specific Cushing's syndrome with central obesity and impaired glucose homeostasis. DESIGN, PATIENTS, AND METHODS: Clinical and laboratory characteristics, and anthropometric measurements were determined in 15 male and 6 female obese pubertal children (aged 12-18 years, Tanner stages 2-5). In addition, analyses of 24-h excretion rates of glucocorticoids were also performed in 21 age-, sex-, and pubertal stage-matched non-obese children using gas chromatographic-mass spectrometric (GC-MS) analysis. RESULTS: 11beta-HSD1 activity (urinary tetrahydrocortisol (THF) + 5alpha-THF/tetrahydrocortisone (THE) ratio) was lower in obese when compared with non-obese boys. In addition, obese children had a higher total cortisol metabolite excretion than non-obese children. 11beta-HSD1 activity was significantly related to age in lean and obese children. Standard deviation score (SDS)-body mass index did not correlate with 11beta-HSD1 activity, or with total cortisol metabolite excretion within each group. In obese children, 11beta-HSD1 activity and total cortisol metabolite excretion showed no correlation to waist-to-hip ratio, fat mass (percentage of body mass), or the homeostasis model assessment of insulin resistance index. CONCLUSIONS: In conclusion, our findings strongly suggest that 11beta-HSD1 activity increases with age, and is reduced in obese boys. In addition, obese children have a higher total cortisol metabolites excretion suggesting a stimulated hypothalamus-pituitary-adrenal axis.