Evaluation of a targeted prodrug strategy of enhance oral absorption of poorly water-soluble compounds.
Pharm Res
; 15(7): 1012-8, 1998 Jul.
Article
in En
| MEDLINE
| ID: mdl-9688053
ABSTRACT
PURPOSE:
The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound.METHODS:
Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose.RESULTS:
Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug.CONCLUSIONS:
Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prodrugs
/
Intestinal Absorption
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Pharm Res
Year:
1998
Document type:
Article
Affiliation country:
United States