The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

This study demonstrates that pretreatment with a potent and selective LTD4 antagonist markedly attenuates exercise-induced bronchoconstriction, and it suggests that LTD4 is a major mediator of this type of bronchoconstriction.

ABSTRACT:The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [ 14 C]rofecoxib (125 mg, 100 Ci) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that the t max was achieved at 9 h postdose. After t max , levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effective t (Prasit et al., 1999), an inducible isoform of cyclooxygenase that plays a key role in inflammatory processes. Rofecoxib has been approved for the treatment of arthritis and pain, and was developed on the premise that selective inhibition of COX-2 would result in decreased inflammation without the adverse gastrointestinal effects associated with inhibition of COX-1 (Vane and Botting, 1996; Donnelly and Hawkey, 1997; Jouzeau et al., 1997). This hypothesis has been supported by the results of recent clinical trials, including the VIGOR study, in which rheumatoid arthritis patients treated with rofecoxib displayed significantly fewer clinically important gastrointestinal events than patients treated with naproxen, a nonselective COX inhibitor (Bombardier et al., 2000).1Disposition and metabolism of rofecoxib in rats and dogs were reported recently (Halpin et al., 2000); metabolites identified in both species included 5-hydroxyrofecoxib, 5-hydroxyrofecoxib-O-␤-Dglucuronide, and trans-3,4-dihydro-rofecoxib, while additional metabolites identified in rat only were cis-3,4-dihydro-rofecoxib, rofecoxib-3Ј,4Ј-dihydrodiol, and 4Ј-hydroxyrofecoxib sulfate. Of note, following oral administration of rofecoxib to intact rats, was the appearance of a second C max which was not observed in bile duct-cannulated rats. This phenomenon was found to be due to a novel form of enterohepatic recycling, which involved reversible metabolism of rofecoxib to 5-hydroxyrofecoxib (Baillie et al., 2001).The studies presented here describe the disposition and metabolism of rofecoxib in human subjects. The specific objectives of these studies were: 1) to examine the absorption and excretion of [ 14 C]rofecoxib in healthy adult volunteers and to compare the results with those obtained from animals, 2) to identify the urinary metabolites of rofecoxib in humans, 3) to examine the extent of conversion of 5-hydroxyrofecoxib to rofecoxib following oral administration of 5-hydroxyrofecoxib to healthy subjects, and 4) to investigate the possible involvement of biliary elimination in the excretion of rofecoxib and its metabolites in humans.

In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

The single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, were examined in two clinical studies. Single-dose pharmacokinetics--including dose proportionality, absolute bioavailability of the highest dose-strength (120-mg) tablet, and the effect of a high-fat meal on the bioavailability of that tablet--were investigated in a two-part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady-state pharmacokinetics were investigated in an open-label study in which 24 healthy subjects were administered 120-mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high-fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady-state pharmacokinetics of etoricoxib, achieved following 7 days of once-daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once-daily dosing. Etoricoxib was generally well tolerated.

Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR. The approximately 8% increase in INR at steady state with warfarin co-administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin.

Twelve healthy male volunteers received single market-image 40-mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (a beta-hydroxyacid) at 1 week intervals in a three-way crossover study to quantify HMG-CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG-CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG-CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2-3 fold greater area under the concentration-time curve) suggest a greater potential availability of pravastatin-related inhibitory activity to peripheral tissues.

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