TY - JOUR
T1 - Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen
AU - Yamakawa, Naoki
AU - Suemasu, Shintaro
AU - Watanabe, Hiroshi
AU - Tahara, Kayoko
AU - Tanaka, Ken ichiro
AU - Okamoto, Yoshinari
AU - Ohtsuka, Masami
AU - Maruyama, Toru
AU - Mizushima, Tohru
N1 - Funding Information:
Received May 24, 2012; Accepted July 31, 2012 J-STAGE Advance Published Date: August 14, 2012, doi:10.2133/dmpk.DMPK-12-RG-050 *To whom correspondence should be addressed: Tohru MIZUSHIMA, Ph.D., Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Tel. ©81-3-5400-2628, Fax. ©81-3-5400-2628, E-mail: mizushima-th@pha.keio.ac.jp This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid from the Japan Science and Technology Agency.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Gastric lesions
KW - Liver homogenates
KW - Loxoprofen
KW - Pharmacokinetics
KW - Rat
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U2 - 10.2133/dmpk.DMPK-12-RG-050
DO - 10.2133/dmpk.DMPK-12-RG-050
M3 - Article
C2 - 22892443
AN - SCOPUS:84876768292
VL - 28
SP - 118
EP - 124
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 2
ER -