Corticosteroid‐binding globulin regulates cortisol pharmacokinetics

SummaryObjective  Corticosteroid‐binding globulin (CBG) is the principal carrier for cortisol in the circulation. Variations in CBG‐binding capacity are predicted to alter total serum cortisol disposition, but free serum cortisol is believed to be unaffected. Unbound cortisol pharmacokinetics (PK) have not been studied in the context of CBG changes. We aimed to assess the regulation of cortisol PK by CBG.Design and subjects  Women on oestrogens [oral contraceptive pill, (OCP)], patients homozygous for a nonfunctioning CBG variant (CBG null) and healthy controls (HV) were studied before and after IV and oral administration of hydrocortisone 20 mg.Measurements  PK parameters were studied for total serum cortisol (SerF), free serum cortisol (FreeF) and cortisone (FreeE), and salivary cortisol (SalF) and cortisone (SalE): area under the curve (AUC), clearance (CL), half‐life and volume of distribution (Vd).Results  Following IV hydrocortisone, AUC and half‐life of SerF were significantly higher in the OCP group and lower in the CBG null. SerF CL and Vd were significantly lower in the OCP group and increased in the CBG null, compared to HV. PK parameters for FreeF and the salivary biomarkers were not different between the CBG null and HV, although OCP patients still had higher AUC compared to HV and prolonged half‐life. These findings were confirmed following oral hydrocortisone, but concentration–time profiles were highly heterogeneous and SalF interpretation was problematic because of oral contamination.Conclusions  We have demonstrated that CBG has a distinct effect on cortisol PK. When CBG binding is disrupted, FreeF retains normal PK characteristics, although CBG null patients lack a CBG‐bound pool of readily releasable cortisol. Women on oestrogens may have altered free serum cortisol kinetics and thus may be potentially overexposed to glucocorticoids.