Clinical pharmacokinetics of nabumetone - The dawn of selective cyclo-oxygenase-2 inhibition?

被引:44
作者
Davies, NM [1 ]
机构
[1] Univ Calgary, Fac Med, Dept Pharmacol & Therapeut, Intestinal Dis Res Unit, Calgary, AB T2N 4N1, Canada
关键词
D O I
10.2165/00003088-199733060-00001
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) of the 2,6-disubstituted naphthyl-alkanone class. Nabumetone is metabolised to an active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) which is a relatively selective cyclo-oxygenase-2 inhibitor that has anti-inflammatory and analgesic properties. Nabumetone and its metabolites bind extensively to plasma albumin. Nabumetone is eliminated following biotransformation to 6-MNA, which does not undergo enterohepatic circulation and the respective glucoroconjugated metabolites are excreted in urine. Substantial concentrations of 6-MNA are attained in synovial fluid, which is the proposed site of action in chronic inflammatory arthropathies. A smaller area under the plasma concentration-time curve (AUC) is evident at steady state as compared with a single dose; this is possibly due to an increase in the volume of distribution and saturation of protein binding. Relationships between 6-MNA concentrations and the therapeutic and toxicological effects have yet to be elucidated for this NSAID. Renal failure significantly reduces 6-MNA elimination but steady-state concentrations of 6-MNA are not increased, possibly because of nonlinear protein binding. Elderly patients with osteoarthritis demonstrate decreased elimination and increased plasma concentrations of nabumetone as compared with young healthy volunteers. Rheumatic disease activity also influences 6-MNA plasma concentrations, as patients with more active disease and lower serum albumin concentrations demonstrate a lower area under the plasma concentration versus time curve. A reduced bioavailability of 6-MNA in patients with severe hepatic impairment is also evident. Dosage adjustment may be required in the elderly, patients with active rheumatic disease and those with hepatic impairment, but not in patients with mild-to-moderate renal failure.
引用
收藏
页码:403 / 416
页数:14
相关论文
共 45 条
  • [1] A randomized, double-blind, crossover comparative endoscopy study on the gastroduodenal tolerability of a highly specific cyclooxygenase-2 inhibitor, flosulide, and naproxen
    Bjarnason, I
    Macpherson, A
    Rotman, H
    Schupp, J
    Hayllar, J
    [J]. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 1997, 32 (02) : 126 - 130
  • [2] IMPORTANCE OF LOCAL VERSUS SYSTEMIC EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS IN INCREASING SMALL INTESTINAL PERMEABILITY IN MAN
    BJARNASON, I
    FEHILLY, B
    SMETHURST, P
    MENZIES, IS
    LEVI, AJ
    [J]. GUT, 1991, 32 (03) : 275 - 277
  • [3] BLOWER P, 1991, EUR J RHEUMATOL INFL, V11, P37
  • [4] NABUMETONE PHARMACOKINETICS IN PATIENTS WITH VARYING DEGREES OF RENAL IMPAIRMENT
    BOELAERT, JR
    JONNAERT, HA
    DANEELS, RF
    SCHURGERS, ML
    THAWLEY, AR
    UNDRE, NA
    COOPER, DL
    [J]. AMERICAN JOURNAL OF MEDICINE, 1987, 83 (4B) : 107 - 109
  • [5] BOURKE B, 1985, ROYAL SOC MED INT C, V69, P31
  • [6] NABUMETONE - EVIDENCE FOR THE LACK OF ENTEROHEPATIC CIRCULATION OF THE ACTIVE METABOLITE 6-MNA IN HUMANS
    BRETT, MA
    BUSCHER, G
    ELLRICH, E
    GREB, WH
    KURTH, HJ
    RULANDER, G
    SCHMERENBECK, B
    HADDOCK, RE
    THAWLEY, AR
    [J]. DRUGS, 1990, 40 : 67 - 70
  • [7] BRIER ME, 1990, CLIN RES, V38, pA520
  • [8] POPULATION PHARMACOKINETICS OF THE ACTIVE METABOLITE OF NABUMETONE IN RENAL DYSFUNCTION
    BRIER, ME
    SLOAN, RS
    ARONOFF, GR
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1995, 57 (06) : 622 - 627
  • [9] BIOEQUIVALENCE STUDY OF NABUMETONE - TABLET VERSUS SUSPENSION
    DAIGNEAULT, EA
    FERSLEW, KE
    STANTON, P
    [J]. AMERICAN JOURNAL OF MEDICINE, 1987, 83 (4B) : 11 - 14
  • [10] Clinical pharmacokinetics of nabumetone - The dawn of selective cyclo-oxygenase-2 inhibition?
    Davies, NM
    [J]. CLINICAL PHARMACOKINETICS, 1997, 33 (06) : 403 - 416