Comparison of pharmacokinetics of loxoprofen and its active metabolites after an intravenous, intramuscular, and oral administration of loxoprofen in rats: evidence for extrahepatic metabolism.
The objective of this study was to characterize the extent of the formation of the active (trans-alcohol form) and inactive (cis-alcohol) metabolites of loxoprofen and to compare the kinetics after its intragastric, intravenous, and intramuscular administrations in rats. After intravenous administration of the drug at doses of 5-20 mg/kg, the clearance and the volume of distribution for loxoprofen, and the ratios of the AUC for the metabolites to the parent drug were not statistically different with the dosage; the formation clearances were 1.08 and 0.87 mL/min/kg for the active and its isomeric metabolite, respectively. After the intragastric, intravenous, or intramuscular administration, AUC for loxoprofen and the metabolites at a dose of 10 mg/kg were not statistically different for the different routes of administration. The formation of the metabolites with the concomitant loss of loxoprofen was found in incubations with liver homogenates and blood but not with a muscle homogenate or plasma, indicating that the conversion of loxoprofen to the metabolites may occur both in the liver and extraheptic tissue(s). Thus, approximately 22% of the loxoprofen may have been converted to the active metabolite in the liver and the extraheptic tissue(s) and the pharmacokinetics of the active metabolite was independent of the route of administration.
Koo
Tae-Sung
TS
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Kim
Dae-Hyun
DH
Ahn
Sung-Hoon
SH
Kim
Kang-Pil
KP
Kim
In-Wha
IW
Seo
Seung-Yong
SY
Suh
Young-Ger
YG
Kim
Dae-Duk
DD
Shim
Chang-Koo
CK
Chung
Suk-Jae
SJ
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004912:Erythrocytes / Q000378:metabolism*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009132:Muscles / Q000378:metabolism*; D010666:Phenylpropionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; C040656:loxoprofen