Abstract
Introduction
Osteonecrosis of the femoral head (ONFH) is one of the most serious complications associated with corticosteroid therapy. In patients with ONFH, collapse of the femoral head often occurs and causes severe hip pain and impaired hip joint function. Despite the widely spread use of corticosteroids for treating various diseases and a known association between prevalence of ONFH and daily dose of corticosteroids, the pathomechanism for the development of ONFH has not been identified. Since hepatic cytochrome P4503A (CYP3A) is a predominant enzyme responsible for metabolizing corticosteroids and its activities varies more than 10-fold, low hepatic CYP3A activity leads to a remarkable increase of corticosteroid levels and its effect. We have previously reported that hepatic CYP3A levels are significantly lower in patients with corticosteroid-induced ONFH than that in control patients and patients with alcohol-related ONFH and that hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids in a rabbit model, suggesting possible prevention of the corticosteroid-induced osteonecrosis by adjusting corticosteroid dose based on the level of individual hepatic CYP3A activity prior to corticosteroid therapy. To examine hepatic CYP3A activity, measuring clearance of administrated midazolam (MDZ) is a reliable method, as shown by the significant correlations between the clearance of midazolam and hepatic CYP3A levels measured by biopsy and the clearance of other CYP3A-specific substrates. However, the method is invasive and time consuming for measuring clearance of administrated MDZ, needing multiple blood samplings over half a day for each subject. The aim of this study was to develop the simple, safe and noninvasive methods for measuring the level of hepatic CYP3A activity, which is applicable to prevent the occurrence of corticosteroid-induced osteonecrosis prior to corticosteroid therapy.
Methods
Thirty seven healthy male (n=20) and female (n=17), volunteers who had a mean age of 27 years received single oral administration of a small quantity of midazolam (50 mg/kg) and concentrations of total midazolam and its principal metabolite, 1-hydroxymidazolam (1-OH-midazolam), in each plasma at 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 9 and 12 hours post-drug administration were measured. Secondarily, the assessment of the Observer's Assessment of Alertness/Sedation (OAA/S) Scale was also used during the 12-hour post-administration period.
Results
The best correlations between midazolam clearance and the ratio of 1- OH- midazolam/ midazolam plasma concentrations measured at each experimental time were observed at 4 hours (R2 = 0.83) post-dosing, and better correlations were found at 3 hours with a strong correlation (R2 = 0.81). Good correlations between midazolam clearance and OAA/S scale were found at 15 minutes (p = 0.04).
Conclusion
A single midazolam plasma measurement taken at 4 hours post-oral administration may represent an accurate marker of CYP3A activity. This simple, safe and noninvasive method for measuring CYP3A activity could be used for patients prior to corticosteroid therapy, and the adjusting dose of corticosteroids, tailor-made medicine, depending on the CYP3A activity of the individual patient could avoid the occurrence of corticosteroid-induced osteonecrosis.
