Disposition of ibuprofen in patients with liver cirrhosis. Stereochemical considerations.
Following a single oral dose of racemic ibuprofen 600mg the stereoselective disposition of its enantiomers was studied in 8 patients with moderate to severe cirrhosis. Compared with the elimination half-life (t1/2) of (-)-R- and (+)-S-ibuprofen in 8 healthy age-matched controls (1.7 +/- 0.3h and 1.8 +/- 0.5h, respectively), t1/2 was prolonged significantly (p < 0.045 and < 0.001, respectively) in patients with cirrhosis (t1/2 = 3.1 +/- 1.7h and 3.4 +/- 1.0h, respectively). Whereas the low amounts excreted unchanged into urine differed slightly in both groups studied, much less (p < 0.01) conjugated ibuprofen was recovered either as the R-enantiomer (0.9 +/- 0.4% vs 4.1 +/- 2.8% of the dose) or the S-enantiomer (6.4 +/- 2.5% vs 26.5 +/- 12.9% of the dose) in patients with cirrhosis. Metabolic inversion of the inactive (-)-R-ibuprofen to the active (+)-S-ibuprofen may be impaired in hepatic dysfunction since the normal ratio of areas under the curve (AUC) for R- and S-enantiomers (0.79 +/- 0.18) was significantly (p < 0.02) higher in patients with cirrhosis (1.10 +/- 0.28). In a second study, a single oral dose of 400mg (+)-S-ibuprofen was administered to 8 healthy volunteers and 8 patients with cirrhosis. Elimination of this enantiomer was slightly impaired as could be seen from the prolonged t1/2 (1.6 +/- 0.1h vs 2.6 +/- 0.5h; p < 0.001) and the increase in AUC (101 +/- 35 vs 144 +/- 41 mg/L.h; p = 0.041). In conclusion, in patients with liver disease, hepatic elimination of ibuprofen is impaired. This should be taken into consideration especially if the racemic drug is used. Direct administration of the active (+)-S-enantiomer seems to offer less vulnerable treatment.
Li
G
G
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Federal Republic of Germany.
Treiber
G
G
Maier
K
K
Walker
S
S
Klotz
U
U
D000328:Adult; D000368:Aged; D005260:Female; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism
D007052:Ibuprofen