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Steroid Carboxylic Acids
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
We have administered (1,23H)-20β-isocortisol or (1,23H)-20β-isotetrahydrocortisone admixed with (4-14C)-cortisol to human subjects;258 in other cases (4-14C, 20α-3H) isocortisol was administered. The isolation of 20-hydroxy metabolites as the predominant products isolated after the administration of the isosteroids proves that oxidation or reduction at C-21 proceeds more rapidly than isomerization back to the isomeric ketol (Table 9). This is further supported by the absence of tetrahydrocortisol (THF) and tetrahydrocortisone (THE) as metabolites of the isosteroids.258 This pattern is quite different from that which occurs after the administration of cortisol or cortisone.259 Some epimerization of C-20 takes place as evidenced by the formation of a-cortol and a-cortolonic acid. The retention of 3H in the 20a compounds isolated following the administration of the 20α3H, 20β OH-labeled isosteroids suggests a direct epimerization rather than oxidation and reduction at C-20. The absence of the 20-keto metabolites THF and THE further supports this mechanism. The yield of acids from the isosteroids was lower than from the ketols. This was due to rapid transformation of the iso compounds to complexes which remained in the residual urine (Table 10).
Hydrocortisone granules in capsules for opening (Alkindi) as replacement therapy in pediatric patients with adrenal insufficiency
Published in Expert Opinion on Orphan Drugs, 2021
Helen Coope, Lotta Parviainen, Mike Withe, John Porter, Richard J Ross
Hydrocortisone has been used in humans for more than 60 years and is identical to the innate hormone cortisol. Like other steroids, cortisol binds to an intracellular receptor which, after migrating to the nucleus of the cell, upregulates or downregulates gene expression. Hydrocortisone also acts through non-genomic mechanisms [42]. Hydrocortisone is rapidly and virtually completely absorbed from the fasted alimentary system (bioavailability is ~100%) with Tmax reached about 60 minutes [43]. Cortisol is highly protein bound mostly by cortisol binding globulin, with a smaller amount of albumin binding. This leads to non-linear pharmacokinetics as higher doses of hydrocortisone are more rapidly cleared due to saturation of the protein binding [43,44]. Metabolism of cortisol is by renal 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) to inactive cortisone whilst hepatic and adipose 11β-HSD1 converts cortisone to cortisol. Cortisol, cortisone and downstream metabolites allo-tetrahydrocortisol, tetrahydrocortisol and tetrahydrocortisone, are all renally excreted [45].
Novel insights into the pharmacometabonomics of first-line tuberculosis drugs relating to metabolism, mechanism of action and drug-resistance
Published in Drug Metabolism Reviews, 2018
As mentioned earlier, RIF activates PXR, a member of the nuclear receptor superfamily of ligand-dependent transcription factors. The activated PXR in turn binds to the response elements in the promotors and upregulates the transcription of specific transporters and drug metabolizing enzymes, including that of the CYPs (Ramappa and Aithal 2013), with as much as 7.7-fold (Rae et al. 2001). With the aim of identifying changes to the endogenous metabolite concentrations associated with RIF-induced PXR activation, Cho et al. (2009) compared the urinary metabolite profiles of pxr-humanized mice receiving a RIF-containing diet (10 mg/kg/d) to those receiving a control diet, using a UPLC-TOFMS metabolomics approach. Results indicated significantly reduced levels of two urinary vitamin E (tocopherol) metabolites; α-carboxyethyl hydroxychroman (CEHC) glucuronide and γ-CEHC β-D-glucoside (Table 2), which is presumably an outcome of a PXR-mediated repression of hepatic sterol carrier protein 2 (which is involved in peroxisomal β-oxidation of branched-chain fatty acids) (Figure 2), since these metabolite variations were not detected when using pxr-null mice. For the same purpose, Kim et al. (2013) applied global metabolic profiling (via UPLC/QTOF-MS analyses) and semi-targeted steroid profiling (via GC-MS analyses) of urine samples collected from 12 healthy human male subjects before and after RIF ingestion. The aforementioned global metabolomics analyses of the two groups indicated significantly increased levels of glycochenodeoxycholate sulfate and hydroxytestosterone sulfate, accompanied by vastly reduced levels of dehydroepiandrosterone (DHEA) sulfate, androsterone sulfate, and p-cresol, after RIF ingestion. The semi-targeted urinary steroid analyses revealed elevated concentrations of 16α-OH-A-dione, 16α-OH-DHEA, 7α-DHEA, 7β-DHEA and 11β-OH-A-dione and reduced levels of DHEA, androsterone, etiocholanolone, estrone, β-cortolone, and allo-tetrahydrocortisone in the RIF group (Table 2). These results suggest that the RIF-induced PXR-activation inhibits CYP17A/19A and activates CYP1A/3A/7B/11B/2C. It was furthermore suggested that these metabolite markers and their ratios could potentially be used for predicting the extent of PXR activation, to monitor the activities of various drug-metabolizing enzymes and/or to predict drug-drug interactions (Kim et al. 2013).