Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 118-124 |
| Number of pages | 7 |
| Journal | Drug Metabolism and Pharmacokinetics |
| Volume | 28 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2013 |
| Externally published | Yes |
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Keywords
- Gastric lesions
- Liver homogenates
- Loxoprofen
- Pharmacokinetics
- Rat
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology
- Pharmaceutical Science
Cite this
Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen. / Yamakawa, Naoki; Suemasu, Shintaro; Watanabe, Hiroshi; Tahara, Kayoko; Tanaka, Ken ichiro; Okamoto, Yoshinari; Ohtsuka, Masami; Maruyama, Toru; Mizushima, Tohru.
In: Drug Metabolism and Pharmacokinetics, Vol. 28, No. 2, 2013, p. 118-124.Research output: Contribution to journal › Article
}
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
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
UR - http://www.scopus.com/inward/record.url?scp=84876768292&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876768292&partnerID=8YFLogxK
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 -