THE IN-VITRO EFFECTS OF 6-METHOXY-2-NAPHTHYLACETIC ACID, THE ACTIVE METABOLITE OF NABUMETONE, ON RAT GASTRIC-MUCOSAL EICOSANOID SYNTHESIS AND METABOLISM
R. Melarange et al., THE IN-VITRO EFFECTS OF 6-METHOXY-2-NAPHTHYLACETIC ACID, THE ACTIVE METABOLITE OF NABUMETONE, ON RAT GASTRIC-MUCOSAL EICOSANOID SYNTHESIS AND METABOLISM, Prostaglandins, leukotrienes and essential fatty acids, 55(3), 1996, pp. 195-200
Nabumetone is a neutral non-steroidal anti-inflammatory drug with a lo
w propensity to cause gastrointestinal (GI) damage. Previous studies,
in vivo, have shown that the drug has weak effects on gastric mucosal
cyclooxygenase activity, which may help to explain its favourable GI p
rofile. The present study set out to determine whether the observed ef
fects of nabumetone on cyclooxygenase, in vivo, parallel those of its
active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA), in vitro. W
e have also studied nabumetone and 6MNA on two other systems, namely 1
5-prostaglandin dehydrogenase (15-PGDH) and 5-lipoxy-genase (5-LO), wh
ich when inhibited may confer mucosal protection. The results showed t
hat 6MNA had variable effects on cyclooxygenase activity, depending on
the concentration and was less potent and less effective than indomet
hacin. Cyclooxygenase activity was not inhibited by the reversible inh
ibitor, aminopyrine, but at low concentrations stimulation was observe
d. Sulphasalazine inhibited 15-PGDH in a concentration-dependent manne
r whereas 6MNA inhibited it only at high concentrations. Nabumetone wa
s devoid of activity. Basal 5-LO activity was attenuated by phenidone
and unaltered by 6MNA but increased by nabumetone at the highest conce
ntration. In the presence of arachidonic acid, to raise 5-LO activity,
nabumetone, 6MNA, BW755C and phenidone apparently inhibited this acti
vity. However, it was possible that both nabumetone and 6MNA inhibited
a prostanoid-mediated stimulatory effect on 5-LO rather than effectin
g enzyme inhibition per se. Nabumetone's favourable GI profile may, th
erefore, relate to 6MNA having weak effects on mucosal cyclooxygenase
and is unlikely to involve inhibition of prostanoid metabolism or 5-LO
.