Abstract
ContextThe assessment absolute bioavailability of oral hydrocortisone is complicated by its saturable binding to cortisol binding globulin (CBG). Previous assessment of bioavailability used a cortisol radioimmunoassay which has cross reactivity with other steroids. Salivary cortisone is a measure of free cortisol and LC-MS/MS is the gold standard method for measuring steroids. We here report the absolute bioavailability of hydrocortisone calculated using serum cortisol and salivary cortisone measured by LC-MS/MS.Methods14 healthy male dexamethasone suppressed volunteers were administered 20 mg hydrocortisone either intravenously or orally by tablet. Samples of serum and saliva were taken and measured for cortisol and cortisone by LC-MS/MS. Serum cortisol was corrected for saturable binding using published data and pharmacokinetic parameters derived using the program WinNonlin.ResultsThe mean (95% CI) bioavailability of oral hydrocortisone calculated from serum cortisol, unbound serum cortisol and salivary cortisone was 1.00 (0.89-1.14); 0.88 (0.75-1.05); and 0.93 (0.83-1.05), respectively.ConclusionThe data confirm that, after oral administration, hydrocortisone is completely absorbed. The data derived from serum cortisol corrected for protein binding, and that from salivary cortisone, are similar supporting the concept that salivary cortisone reflects serum free cortisol levels and that salivary cortisone can be used as a non-invasive method for measuring the pharmacokinetics of hydrocortisone.
Highlights
The assessment of bioavailability of oral hydrocortisone is complicated by its saturable binding in the therapeutic range to cortisol binding globulin (CBG)
The mean bioavailability of oral hydrocortisone calculated from serum cortisol, unbound serum cortisol and salivary cortisone was 1.00 (0.89-1.14); 0.88 (0.75-1.05); and 0.93 (0.83-1.05), respectively
The data derived from serum cortisol corrected for protein binding, and that from salivary cortisone, are similar supporting the concept that salivary cortisone reflects serum free cortisol levels and that salivary cortisone can be used as a non-invasive method for measuring the pharmacokinetics of hydrocortisone
Summary
The assessment of bioavailability of oral hydrocortisone is complicated by its saturable binding in the therapeutic range to cortisol binding globulin (CBG). Ninety percent of serum cortisol circulates bound to cortisol binding globulin, 5% to generic binding proteins, such as albumin and α-1 glycoprotein, and only 5% is unbound or ‘free’ [1]. CBG has high affinity for cortisol but lower capacity whereas albumin has a lower affinity and higher capacity and Lentjes and Romijn published Data from which free unbound cortisol could be calculated [2]. An increase in the free fraction results in an increase in clearance with dose and less than dose proportional increases in Cmax and bioavailability as measured by area under the curve (AUC) [3]. Immunoassays have seen shown to give variable results depending on the specificity and sensitivity of the antibody used and LC-MS/MS is the gold standard method for measuring steroids [4]
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