Halpin R A, Geer L A, Zhang K E, Marks T M, Dean D C, Jones A N, Melillo D, Doss G, Vyas K P
Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey, USA.
Drug Metab Dispos. 2000 Oct;28(10):1244-54.
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).
用罗非昔布（万络，MK - 0966，一种强效且高度选择性的环氧化酶 - 2（COX - 2）抑制剂）在大鼠和狗身上进行了吸收、分布、代谢及排泄研究。在大鼠中，静脉注射或口服[(14)C]罗非昔布后，罗非昔布血药浓度 - 时间曲线终末相（4至10小时时间间隔）呈非指数衰减，这使得无法准确测定半衰期、AUC(0 - ∞)（血药浓度 - 时间曲线外推至无穷大时的面积），进而无法准确测定生物利用度。给狗静脉注射[(14)C]罗非昔布后，罗非昔布的血浆清除率、稳态分布容积和消除半衰期分别为3.6 ml/min/kg、1.0 l/kg和2.6小时。两种动物口服吸收（5 mg/kg）均迅速，大鼠在0.5小时、狗在1.5小时达到C(max)。狗的生物利用度为26%。静脉注射（1、2和4 mg/kg）或口服（2、5和10 mg/kg）给药后，大鼠和狗的全身暴露量均随剂量增加而增加，但在大鼠中，5 mg/kg和10 mg/kg剂量之间未观察到进一步增加。放射性迅速分布到组织中，静脉注射剂量后，大多数组织在5分钟时达到最高浓度，肝脏、皮肤、脂肪、前列腺和膀胱在30分钟时达到最高浓度。除给狗静脉注射[(14)C]罗非昔布后排泄经胆汁和肾脏两条途径外，大鼠和狗的排泄主要通过胆汁途径。罗非昔布的代谢广泛。5 - 羟基罗非昔布 - O - β - D - 葡萄糖醛酸是大鼠尿液和胆汁中排泄的主要代谢产物。5 - 羟基罗非昔布、罗非昔布 - 3',4'-二氢二醇和4'-羟基罗非昔布硫酸盐含量较少，而顺式和反式 - 3,4 - 二氢罗非昔布为次要代谢产物。狗的主要代谢产物为5 - 羟基罗非昔布 - O - β - D - 葡萄糖醛酸（尿液）、反式 - 3,4 - 二氢罗非昔布（尿液）和5 - 羟基罗非昔布（胆汁）。
