Effect of clofibrate on the chiral inversion of ibuprofen in healthy volunteers.
OBJECTIVE
To determine the influence of the hypolipidemic drug clofibrate on the stereoselective metabolism of ibuprofen in humans.


METHODS
Healthy male subjects (n = 12) ingested a dose of 400 mg pseudoracemic ibuprofen (200 mg R-ibuprofen, 160 mg S-ibuprofen, and 40 mg 13C-S-ibuprofen) on two occasions after either pretreatment with clofibrate (2 gm/day over 1 week) or no pretreatment in a randomized order.


RESULTS
When subjects were pretreated with clofibrate, clearances of R-ibuprofen and 13C-S-ibuprofen increased significantly from 55.0 and 66.4 ml/min to 186.2 and 106.7 ml/min (p < 0.01), respectively. This increase was similarly reflected in the clearance by inversion of R-ibuprofen (control, 36.0 ml/min; treated, 118.8 ml/min; p < 0.01), as well as in the clearance by noninversion (control, 19.0 ml/min; treated, 67.4 ml/min; p < 0.01). Unbound clearance values significantly increased for R-ibuprofen (control, 19.5 L/min; treated, 38.7 L/min) but not for 13C-S-ibuprofen (11.8 versus 10.6 L/min, respectively). The fractional inversion of ibuprofen calculated from the urinary metabolite data was increased after clofibrate pretreatment (clofibrate group, 66.4%; control, 53.5%; p < 0.01). However, this was not evident when fractional inversion was calculated from the plasma concentration-time data for the unmetabolized drug.


CONCLUSIONS
Clofibrate altered the stereoselective disposition of ibuprofen in healthy volunteers by increased formation of R-ibuprofenoyl-coenzyme A rather than by an effect on oxidative metabolism of ibuprofen. This interaction has potential therapeutic implications.
Scheuerer
S
S
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen, Germany.
Hall
S D
SD
Williams
K M
KM
Geisslinger
G
G
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D002994:Clofibrate / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D006801:Humans; D000960:Hypolipidemic Agents / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D007052:Ibuprofen / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D012016:Reference Values; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000960:Hypolipidemic Agents; D002994:Clofibrate; D007052:Ibuprofen