Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen.
We recently reported that, compared to loxoprofen (LOX, an non-steroidal anti-inflammatory drug), the LOX derivative fluoro-loxoprofen (F-LOX) is less ulcerogenic but has similar anti-inflammatory activity. Our previous in vitro studies suggested that both LOX and F-LOX are pro-drugs, the active metabolites of which are their trans-alcohol forms. In this study, we compared the pharmacokinetics of F-LOX and LOX in rats. Overall, the pharmacokinetic characteristics of F-LOX, including the formation of metabolites in vivo and in vitro, were comparable to those of LOX. However, F-LOX disappeared from the plasma more rapidly than LOX, which could potentially explain its lower ulcerogenicity. However, we showed that F-LOX produced fewer gastric lesions than LOX, even when a higher plasma concentration of F-LOX was maintained. Similar to LOX, F-LOX was readily metabolized to its trans- and cis-alcohol forms, with a higher level of the trans-alcohol form being observed after oral or intravenous administration of the drug. The preferential formation of the trans-alcohol form was also observed after incubation of F-LOX with rat liver homogenates in vitro. These results suggest that, similar to LOX, F-LOX acts as a pro-drug and that there is a metabolic system that selectively produces its active metabolite.
Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Naoki
N
Yamakawa
Shintaro
S
Suemasu
Hiroshi
H
Watanabe
Kayoko
K
Tahara
Ken-ichiro
K
Tanaka
Yoshinari
Y
Okamoto
Masami
M
Ohtsuka
Toru
T
Maruyama
Tohru
T
Mizushima
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D010666:Phenylpropionates / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; D011355:Prodrugs; C000589306:fluoro-loxoprofen; C040656:loxoprofen