Corticosteroid glucuronides

Studies of the conjugates of cortisol metabolites in the fetal plasma show that a very small percentage arc found as glucuronides (Migeon et al., 1956, 1957a). It is not yet established whether corticosteroid glucuronides can cross the placental barrier. 

At present, the transfers of corticosteroid glucuronides through the placenta are not well known, but it is su csted that there is also a lack of j8-gIucuronidase activity for these steroids in both the placental and fetal compartments. 

The same strategy was applied in colon-specific delivery of two corticosteroids used to treat inflammatory bowel disease [20][21], Indeed, budeso-nide /3-D-glucuronide and dexamethasone /3-D-glucuronide underwent ready hydrolysis in the luminal contents of rat colon and caecum. Rat mucosal homogenates were less active, and hydrolysis in human fecal samples was quite low. Based on these and other studies, the prodrugs were found to be suitable candidates for delivery of corticosteroids to the large intestine. 

Mycophenolate mofetil (CdlCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an inactive glucuronide. 

Corticosteroid metabolites are excreted in the urine by the kidneys mainly as glucuronides and sulfates, but also as non-conjugated products. Small amounts of non-metabolized drugs are also excreted in the urine, while negligible amounts of most of the drugs are excreted in the bile. 

Similar to glycoside prodrugs are the glucuronide prodrugs containing corticosteroids [53-55], They also show improvements in the therapeutic effect and in the reduction of side effects. 

Corticosteroids are used by some athletes and racing horses to enhance their performances. In order to prohibit drug doping, many sport organizations, e.g., International Olympic Committee, attempt to monitor the corticosteroids in urine of athletes. An example of earlier GC-MS method in steroid screen consists of procedures of deconjugation of glucuronide and sulfate, derivatization with MSTFA and GC-MS analysis [98], The more recent LC-MS/MS methods separate the corticosteroids by... 

The addition of mycophenolate mofetil to ciclosporin has been found to reduce the incidence of rejection episodes in kidney transplant patients and it is licensed for combined use. From the studies above, ciclosporin appears to reduce the levels of the active metabolite, mycophenolic acid, and increase the levels of the glucuronide metabolite (which is associated with mycophenolate adverse effects). The UK manufacturers point out that as efficacy studies were conducted in patients using ciclosporin, mycophenolate and corticosteroids, the finding that ciclosporin reduces the mycophenolic acid AUC by 19% to 38% does not affect the recommended dose requirements. They also state that ciclosporin pharmacokinetics are not affected by mycophenolate. However, this is in contrast to the studies... 

These compounds, occuring mostly in urine or obtained synthetically, are derivatives of androgens, corticosteroid metabolites and oestrogens they are principally sulphate or phosphate esters or glucuronides (combined with glucuronic acid via a jff-glycosidic link). Their separation in column or paper chromatography has been described earlier (cf. [129]). Synthetic acid esters of steroids with succinic or tetrahydrophthahc acids may be classified here also. 

The saturated Cai compounds are then either conjugated with glucuronic acid and appear in urine as the glucuronides, or they are further broken down. The side chain is split off particularly easily from 17-hydroxy compounds. The products are 17-keto steroids, androsterone, etiocholanolone, and. others, which are also excreted as glucuronides (more rarely as sulfates). The amount of 17-keto steroids in urine can be estimated easily with Zimmermann s color reaction it is useful for the diagnosis of adrenal cortical activity. One should be aware, however, that only a part of the corticosteroid excretion is measured, together vith testosterone inactivation products. Normally, about 10-20 mg per day of 17-keto steroids are excreted. 

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