Enhanced Plasma Concentration by Selective Deuteration of Rofecoxib in Rats

Abstract

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.

Applications of Deuterium in Medicinal Chemistry

“…A range of different competing effects might mask or even reverse the consequences of deuteration, such as different rate-limiting steps in enzyme mechanisms, alternative metabolic routes, or competing nonmetabolic elimination mechanisms rendering the translation of in vitro results to in vivo challenging and highly unpredictable. The case of rofecoxib exemplifies this unpredictability . Indeed, d 5 -rofecoxib ( 9 , Figure ) showed a C max of 4181 μg/L compared to a C max of 2416 μg/L for the nondeuterated compound in male rats after 10 mg/kg dose (po), but the two isotopologs exhibited identical half-life values (4.29 h versus 4.18 h).…”

Deuterium in Drug Discovery and Development

“…Improved PK in rats has been reported for 8, a deuterated analog of rofecoxib [40]. The activities of rofecoxib and 8 for inhibition of cyclooxygenase-1 (COX1) in human platelets were assessed and showed similar IC 50 values of 169 and 173 nM, respectively.…”

Deuterium Isotope Effects on Drug Pharmacokinetics. I. System-Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

“…The effect was attributed to decreased metabolism of p-tyramine by monoamine oxidases. Several reports that have examined the effect of deuteration on the pharmacokinetic and pharmacodynamic properties of drugs reveal results that include little to no effect (Tanabe et al, 1970;Farmer et al, 1979;Taylor et al, 1983;Burm et al, 1988;Dunsaed et al, 1995); increased systemic exposure, a pharmacodynamic effect, and receptor selectivity (Dyck et al, 1988;Schneider et al, 2006Schneider et al, , 2007; and decreased toxicity (Najjar et al, 1978). However, in these studies the mechanisms underlying the observed effects or lack thereof were not examined.…”