Suggestedin VivoIrreversible Metabolism of Labeled Cortisol during Distribution: Effects on Kinetic Measurements and Role of Modes and Sites of Administration
Radioactively labeled cortisol and cortisone were combined, administered iv to human subjects, and 3α,17,21-trihydroxy-5β-pregnane-11, 20-dione (THE) and 3α,1 10,17,21-tetrahydroxy-5β-pregnan-20-one (THF) were determined from the total urinary radioactive metabolites. The presence of 10–60% more of the cortisone-isotope than the cortisol-isotope in THE than in THF suggested that a large portion of the labeled cortisone was reduced to metabolites without entering the cortisol pool.14C-cortisol and 3H-cortisone combined were injected into a right antecubital vein over 30 sec and urine was collected each 15 min. THE had high initial 3H/14C values 260% above the value at equilibrium confirming significant formation of labeled THE prior to essentially complete interconversion of labeled cortisone and cortisol. In contrast, 3H/14C of THF was essentially constant from the outset indicating almost complete interconversion before significant labeled THF formed. Thus, it is postulated that a portion of labeled cortisone formed from, and in proximity to, iv administered labeled cortisol always results in a portion of administered labeled cortisol being irreversibly lost as THE before complete mixing with the cortisol pool, and always tends to produce a higher specific activity for THE than THF in the total urinary metabolites. Serum protein-binding was shown to have only a minor effect on the transformation of labeled cortisol prior to distribution. The role of the site of administration was demonstrated when orally administered labeled cortisol gave rise to much larger increases in THE specific activity relative to THF than did rapid intravenous injection. The importance of the mode of administration was evident when a 4-hr infusion of labeled cortisol showed significantly greater increases in THE specific activity relative to THF than did rapid intravenous administration. The irreversible metabolism of administered labeled cortisol during mixing with the cortisol pool can influence significantly the calculations of production rates and other kinetic parameters by isotope dilution procedures. The studies emphasize the need to understand pathways and rates of metabolism of biological substances when analyzing kinetic data.