Evaluation of a targeted prodrug strategy of enhance oral absorption of poorly water-soluble compounds.
OBJECTIVE
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.
Pharmacokinetics and Drug Metabolism Department, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. o.helen.chan@wl.com
O H
OH
Chan
H L
HL
Schmid
L A
LA
Stilgenbauer
W
W
Howson
D C
DC
Horwell
B H
BH
Stewart
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000201:enzymology; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014867:Water
D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs; D014867:Water