No abstract

Triamcinolone acetonide, triamcinolone hexacetonide, and a combination of betamethasone phosphate and acetate were given intra-articularly in different doses. Plasma levels of the steroids were measured and pharmacokinetic parameters were calculated. As a pharmacodynamic parameter for systemic steroid activity, plasma hydrocortisone levels were monitored for 3 weeks. Results indicate complete absorption from the site of injection over a period of 2 to 3 weeks. Because of its lower solubility, triamcinolone hexacetonide is absorbed slower than triamcinolone acetonide, thus maintaining synovial levels for a longer time and creating lower systemic corticoid levels. Endogenous hydrocortisone suppression correlated with exogenous steroid levels. Threshold concentrations for maximum suppression were determined.

The pharmacokinetics of 20 mg hydrocortisone were studied after IV and oral administration. Endogenous hydrocortisone was suppressed by dexamethasone administration. Hydrocortisone concentrations were measured in plasma and saliva. After IV administration, hydrocortisone was eliminated with a total body clearance of 18 L/hr and a half-life of 1.7 hr. The volume of distribution was 34 L. Oral bioavailability averaged 96%. Absorption was rapid, achieving maximum hydrocortisone levels of 300 ng/mL after 1 hour. Saliva levels were not proportional to plasma levels, but could be shown to reflect free, non-protein bound hydrocortisone concentrations in plasma.

The pharmacokinetics of triamcinolone acetonide were studied after intravenous (2 mg), oral (5 mg), and inhaled (2 mg) administration. Triamcinolone acetonide concentrations were measured in plasma by high-performance liquid chromatography/radioimmunoassay. After intravenous administration, triamcinolone acetonide was eliminated with a total body clearance of 37 L/h and a half-life of 2.0 hours. The volume of distribution was 103 L, and oral bioavailability averaged 23%. Absorption was rapid, achieving maximum triamcinolone acetonide levels of 10.5 ng/mL after 1 hour. After inhalation, bioavailability averaged 22% with maximum levels of 2.0 ng/mL observed after 2.1 hours. The resulting systemic levels for all three treatments caused a significant decrease in the number of lymphocytes in blood.

Dexamethasone in form of its phosphate was given intravenously in two different doses (1.5 mg kg-1 and 15 mg). Plasma levels of the ester and dexamethasone were measured and pharmacokinetic parameters were calculated. The results indicate no dose-dependency of the pharmacokinetic parameters in the investigated range for dexamethasone. Conversion from the prodrug to the active form was rapid; maximum dexamethasone plasma concentrations were reached after 10 min. The results were verified by dexamethasone level monitoring in patients after chronic dosing. Predicted and achieved steady state levels agreed well.

Glucocorticoids are predominantly prescribed in asthma therapy as aerosols to achieve high pulmonary effects with reduced systemic spill-over and pronounced pulmonary selectivity. A variety of pharmacokinetic parameters are potentially important for determining pulmonary selectivity. The intent of this article, is to provide a practice-relevant theoretical approach to put the importance of these parameters on pulmonary targeting using pharmacokinetic/pharmacodynamic modeling as a tool in perspective. The applied pulmonary pharmacokinetic/pharmacodynamic model revealed that, in addition to recognized parameters such as systemic clearance, oral bioavailability, and efficiency of pulmonary deposition, other factors, such as the pulmonary release (dissolution) rate and dose, are relevant. However, the volume of distribution (for effect parameters not undergoing a diurnal rhythm) and the receptor affinity of a given glucocorticoid are not important for achieving lung targeting.

To prove the clinical usefulness of cortisol measurements in saliva for the exact assessment of a patient's corticoid status under therapeutic hormone substitution, we measured simultaneously total cortisol in serum and non-protein-bound cortisol in saliva after administration of different forms of hydrocortisone (cortisol) in eight cortisol-suppressed, healthy male volunteers. The intravenous and oral administration of 20 mg of cortisol exceeds the binding capacity of the corticosteroid-binding globulin (CBG), leading to an increase of the ratio between salivary and serum cortisol at the higher cortisol concentrations in blood. After rectal administration of 100 mg of cortisol acetate, the serum cortisol concentration does not exceed the binding capacity of CBG, so the ratio between salivary and serum cortisol remains nearly constant. However, this ratio was higher after rectal administration than after intravenous and oral administration, probably because of weaker binding of the acetate form of cortisol to CBG. Thus, the salivary measurement of the non-protein-bound (i.e., biologically active) cortisol offers a convenient way to monitor the effectiveness of various forms of systemic corticoid substitution.

Budesonide monotherapy was effective in the induction of remission and well tolerated in treatment naïve patients with AIH. It should be further evaluated in prospective controlled trials and should be compared to predniso(lo)ne both in monotherapy and in combination with azathioprine.