Abstract
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, aCmax 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.
Footnotes
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Send reprint requests to: Deborah Nicoll-Griffith, Ph.D., Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, CANADA. H9R 4P8. E-mail:deborah_nicoll_griffith{at}merck.com
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↵1 Current address: Astra Research Centre Canada, 7171 Frederick Banting, St. Laurent, Quebec Canada.
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A preliminary report of this work was presented at the 6th European ISSX Meeting, Gothenburg, Sweden. June 30–July 3, 1997, Abstract 54.
- Abbreviations used are::
- COX
- cyclooxygenase
- CYP
- cytochrome P-450
- DFU
- 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone
- ED50
- effective dose required to inhibit 50% of response
- HPLC/CF-LSIMS
- HPLC/continuous-flow liquid secondary ion mass spectrometry
- DFU-lactol
- 5,5dimethyl-3-(3-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2,5-dihydro-2-furanol
- GI
- gastrointestinal
- Methocel
- methocellulose 400
- IC50
- concentration required to yield 50% inhibition
- NSAID
- nonsteroidal anti-inflammatory drug
- Tris
- tris[hydroxymethyl]aminomethane
- PEG
- polyethyleneglycol
- Received April 27, 1998.
- Accepted September 11, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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