Prednisolone 21-sulfate sodium: a colon-specific pro-drug of prednisolone.
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.
Jung
Yun Jin
YJ
College of Pharmacy, Pusan National University, Pusan 609-735, Korea.
Doh
Min Ju
MJ
Kim
In Ho
IH
Kong
Hye Sik
HS
Lee
Jeoung Soo
JS
Kim
Young Mi
YM
D000284:Administration, Oral; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000378:metabolism*; D004304:Dosage Forms; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013429:Sulfatases / Q000187:drug effects / Q000378:metabolism; D013431:Sulfates / Q000008:administration & dosage / Q000378:metabolism
D004304:Dosage Forms; D011355:Prodrugs; D013431:Sulfates; C012036:sodium sulfate; D011239:Prednisolone; D013429:Sulfatases