The absorption, distribution, metabolism and excretion of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in rats and dogs.
Absorption, distribution, metabolism, and excretion studies were conducted in rats and dogs with rofecoxib (VIOXX, MK-0966), a potent and highly selective inhibitor of cyclooxygenase-2 (COX-2). In rats, the nonexponential decay during the terminal phase (4- to 10-h time interval) of rofecoxib plasma concentration versus time curves after i.v. or oral administration of [(14)C]rofecoxib precluded accurate determinations of half-life, AUC(0-infinity) (area under the plasma concentration versus time curve extrapolated to infinity), and hence, bioavailability. After i.v. administration of [(14)C]rofecoxib to dogs, plasma clearance, volume of distribution at steady state, and elimination half-life values of rofecoxib were 3.6 ml/min/kg, 1.0 l/kg, and 2.6 h, respectively. Oral absorption (5 mg/kg) was rapid in both species with C(max) occurring by 0.5 h (rats) and 1.5 h (dogs). Bioavailability in dogs was 26%. Systemic exposure increased with increasing dosage in rats and dogs after i.v. (1, 2, and 4 mg/kg), or oral (2, 5, and 10 mg/kg) administration, except in rats where no additional increase was observed between the 5 and 10 mg/kg doses. Radioactivity distributed rapidly to tissues, with the highest concentrations of the i.v. dose observed in most tissues by 5 min and by 30 min in liver, skin, fat, prostate, and bladder. Excretion occurred primarily by the biliary route in rats and dogs, except after i.v. administration of [(14)C]rofecoxib to dogs, where excretion was divided between biliary and renal routes. Metabolism of rofecoxib was extensive. 5-Hydroxyrofecoxib-O-beta-D-glucuronide was the major metabolite excreted by rats in urine and bile. 5-Hydroxyrofecoxib, rofecoxib-3',4'-dihydrodiol, and 4'-hydroxyrofecoxib sulfate were less abundant, whereas cis- and trans-3,4-dihydro-rofecoxib were minor. Major metabolites in dog were 5-hydroxyrofecoxib-O-beta-D-glucuronide (urine), trans-3, 4-dihydro-rofecoxib (urine), and 5-hydroxyrofecoxib (bile).
Halpin
R A
RA
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey, USA.
Geer
L A
LA
Zhang
K E
KE
Marks
T M
TM
Dean
D C
DC
Jones
A N
AN
Melillo
D
D
Doss
G
G
Vyas
K P
KP
D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D007783:Lactones / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013450:Sulfones; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib