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Vol. 27, Issue 3, 403-409, March 1999
Merck Frosst Centre for Therapeutic Research, Pointe-Claire - Dorval, Quebec, Canada
The lactol derivative of a lactone cyclooxygenase-2 inhibitor (DFU)
was evaluated in vivo and in vitro for its potential suitability as a
prodrug. DFU-lactol was found to be 10 to 20 times more soluble than
DFU in a variety of aqueous vehicles. After administration of
DFU-lactol at 20 mg kg
1 p.o. in rats, a
Cmax of 7.5 µM DFU was reached in the
plasma. After oral administration, the ED50s of DFU-lactol
in the carrageenan-induced paw edema and lipopolysaccharide-induced
pyresis assays in rats are comparable with the ED50s
observed when dosing with DFU. Incubations of DFU-lactol with rat and
human hepatocytes demonstrated that the oxidation of DFU-lactol can be
mediated by liver enzymes and that a competing pathway is direct
glucuronidation of the DFU-lactol hydroxyl group. Assays with
subcellular fractions from rat liver indicated that most of the
oxidation of DFU-lactol occurs in the cytosolic fraction and requires
NAD(P)+. Human liver cytosol can also support the oxidation
of DFU-lactol to DFU when NAD(P)+ is added to the
incubations. Fractionation of human liver cytosolic proteins showed
that at least three enzymes are capable of efficiently effecting the
oxidation of DFU-lactol to DFU. Incubations with commercially available
dehydrogenases suggest that alcohol and hydroxysteroid dehydrogenases
are involved in this oxidative process. These data together suggest
that lactols may represent useful prodrugs for lactone-containing drugs.
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