Prednisolone 21-sulfate sodium: a colon-specific pro-drug of prednisolone

Abstract

Prednisolone 21-sulfate sodium (PDS) was synthesized as a colon-specific pro-drug of prednisolone with the expectation that it would be stable and non-absorbable in the upper intestine and release prednisolone by the action of sulfatase once it was delivered to the colon. In-vitro/in-vivo properties were investigated using rats as test animals. PDS was chemically stable at pH 1.2, 4.5, 6.8 and 8.0, and the apparent partition coefficient was 0.11 in 1-octanol/pH 6.8 buffer solution at 37 degrees C. PDS was stable on incubation with the contents of the stomach or small intestine. When PDS (0.1 mg equiv. of prednisolone) was incubated with the caecal contents (0.05 g), prednisolone was produced to a maximum 54% of the dose in 6 h and decreased thereafter, which suggested that reduction of the A ring took place in addition to the hydrolysis by sulfatase. After oral administration of PDS, a small portion of prednisolone was recovered from the cecal contents but not from the small intestine. Neither PDS nor prednisolone was detected in the plasma, suggesting that absorption of PDS is limited. The data demonstrate that the sulfate ester can serve as a novel colon-specific pro-moiety by limiting the absorption of the pro-drug in the upper intestine and releasing the active compound by the action of microbial sulfatase in the colon.

Dexamethasone 21-Sulfate Improves the Therapeutic Properties of Dexamethasone Against Experimental Rat Colitis by Specifically Delivering the Steroid to the Large Intestine

“…Therefore, it is thought to be important to select an active agent and a colon-specific promoiety that have a proper metabolic property for design of an efficient colon specific prodrug. Since, in addition to our data showing that a significant amount of DS not only was detected in the cecum but also in the colon of rats, D is relatively resistant to colonic reductive metabolism(s) that can nullify or weaken therapeutic activity of the drug (10,11), it is very likely that a fractional dose of DS administered orally reaches the distal part of the large intestine, where DS produces D. Moreover, it is also possible that D produced from DS at the proximal part (cecum) moves down to the distal large intestine without the metabolic inactivation. However, DS seems to be completely deconjugated to liberate D during the transit of the large intestine as DS was not detectable in the feces collected for 24 h after oral administration of DS.…”

“…Administration of glucocorticoids by the rectal route is often limited by poor patient compliance and the drug is largely confined to the distal region of the colon. To reduce the serious side effects caused by the systemic absorption, development of a colon-specific delivery system of corticosteroids is highly desirable (7)(8)(9)(10)(11). This site-specific delivery of the drugs would increase therapeutic concentration at the target site along with decreasing systemic absorption of the drugs, thereby enhancing therapeutic potency and reducing adverse effects.…”

Susceptibility of glucocorticoids to colonic metabolism and pharmacologic intervention in the metabolism: implication for therapeutic activity of colon-specific glucocorticoid 21-sulfate sodium at the target site

“…As reported, synthesis of Glu‐S compounds was achieved in good yield by the reaction of glucocorticoids with sulfatrioxide‐triethylamine complex in dry pyridine, followed by treating it with concentrated NaCl solution. The ratio of the reactants was critical to the suppression of by‐product formation and the optimum ratio for STT/glucocorticoid varies depending on glucocorticoids [6,16] …”

“…Prodrugs aiming at the delivery of glucocorticoids to the colon have been introduced which use polymers such as dextran or highly hydrophilic small molecules such as glucuronic acid, monosaccharides and sulfuric acid as a colon‐specific pro‐moiety [6–9] . Limited absorption of highly polar molecules and polymers allows the delivery of such prodrugs to the colon.…”

Investigation into drug release from colon-specific azoreductase-activated steroid prodrugs using in-vitro models

“…The prodrug approach to colon targeting is plausible because of the success of 5‐aminosalicylic acid prodrugs such as olsalazine, ipsalazide and basalazide [6–10] . These transit to the colon and are activated by azoreductase activity associated with the luxuriant colonic microflora.…”