Impaired intrinsic chiral inversion activity of ibuprofen in rats with adjuvant-induced arthritis.
1. The effects of adjuvant-induced arthritis on the chiral inversion of 'profens', a type of non-steroidal anti-inflammatory drug, have hardly been investigated. The authors investigated the effects of adjuvant-induced arthritis on the chiral inversion of ibuprofen using freshly isolated rat hepatocytes. 2. S- or R-ibuprofen was incubated with hepatocytes isolated from control and adjuvant-induced arthritis rats in the absence of the serum. In the hepatocyte system the chiral inversion rate constant of R- to S-ibuprofen and the metabolic rate constants of both enantiomers in adjuvant-induced arthritis rats were significantly decreased to about 64-80% of the corresponding values in control rats. In contrast, the addition of serum from each group to the corresponding hepatocyte medium resulted in no significant differences in these rate constants between control and adjuvant-induced arthritis rats. 3. With regard to chiral inversion enzymes, adjuvant-induced arthritis decreased the messenger RNA levels of acyl-coenzyme A synthetase (ACS) isoforms, but not 2-arylpropionyl-CoA epimerase, compared with control rats. 4. Chiral inversion of R- to S-ibuprofen was inhibited by triacsin C, a specific inhibitor of ACS1. 5. The results suggest that adjuvant-induced arthritis induces down-regulation of ACS enzymes involved in chiral inversion of R- to S-ibuprofen in rats.
Uno
S
S
School of Pharmacy, Department of Pharmacy, Kinki University, Higashi-Osaka, Osaka, Japan.
Uraki
M
M
Komura
H
H
Ikuta
H
H
Kawase
A
A
Iwaki
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D007052:Ibuprofen / Q000737:chemistry* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D019998:Racemases and Epimerases; C079564:2-arylpropionyl-CoA epimerase; D003066:Coenzyme A Ligases; D007052:Ibuprofen