Enhanced plasma concentration by selective deuteration of rofecoxib in rats.
The plasma concentrations of BDD-11602 (4-[4- (methanesulfonyl)phenyl]-3-(pentadeuterophenyl)-5H-furan-2-one), a rofecoxib derivative in which the positions 2',3;4',5' and 6' of the phenyl ring were deuterated, and rofecoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one, CAS 162011-90-7) were compared in order to explore the effects of selective deuteration on the systemic availability. The COX-2 selectivity in vitro was also compared. Following oral gavage administration of 0.1, 1 or 10 mg/kg BDD-11602 to Sprague Dawley rats, AUCo-t, (area under the curve) and Cmax (maximum concentration) values were statistically significant higher than those of rofecoxib at the same doses. The overall increase in AUC0-t and Cmax for BDD-11602 over rofecoxib was 1.53-fold and 1.60-fold, respectively. BDD-11602 and rofecoxib inhibited COX-2-derived PGE(2) synthesis with IC50 values of 173 nmol/l and 169 nmol/l, respectively. IC50 values for inhibition of human platelet COX-1 were estimated to be above 1 micromol/l for both compounds. The substitution of hydrogen by deuterium on the positions 2: 3',4',5' and 6' in BDD-11602 leads to superior oral availability compared to the non-deuterated compound, whereas the COX-2 selectivity is not affected.
Schneider
Frank
F
BiRDS Pharma GmbH, Berlin, Germany. fschneider@birdspharma.com
Hillgenberg
Moritz
M
Koytchev
Rossen
R
Alken
Rudolf-Giesbert
RG
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D003903:Deuterium; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007783:Lactones / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics*
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D003903:Deuterium