Disease relevance of l-Ibuprofen

• The results indicate that the fatty liver condition stereoselectively affects (R)-ibuprofen clearance and eliminates preferential (S)-isomer hepatic distribution [1].

High impact information on l-Ibuprofen

• Ratios of IC50 values for cyclooxygenase inhibition by D- and L-ibuprofen, a competitive cyclooxygenase inhibitor, were 32, 67, and 7.1 for native PGHS-1, R120Q PGHS-1, and Y355F PGHS-1, respectively [2].
• The bioavailabilities of (R)-ibuprofen and total ibuprofen were 0.92 +/- 0.11 and 0.95 +/- 0.08, respectively [3].
• Inhibition of nitric oxide synthase [NOS; 100 micromol/l N(G)-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 micromol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 +/- 7%) [4].
• It appeared that the extent of metabolic activation of (R)-ibuprofen to the (S)-isomer in renally compromised patients was greater than that in a normal setting [5].
• Total (R)-ibuprofen clearance (ClRtot), chiral inversion-related clearance (ClRinv), (S)-ibuprofen clearance (ClS) and hepatic distribution coefficients for each stereoisomer (KR and KS) were calculated with a model that corrected for perfusate reservoir sampling [1].

Biological context of l-Ibuprofen

• The presence of the CYP2C8*3 allele was found to influence the pharmacokinetics of (R)-ibuprofen in a gene-dose effect manner [6].
• Additional simulations of S/R AUC ratios, for administration of (-)-(R)-ibuprofen only, ranged from 1.5 (presystemic bioinversion) to 0.66 (systemic bioinversion) [7].
• The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml [8].
• In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)-enantiomer; fraction inverted (+/- SE) was 0.37 +/- 0.05 for (R)-ibuprofen and 0.85 +/- 0.03 for (R)-fenoprofen [9].

Anatomical context of l-Ibuprofen

• In this study, (R)-ibuprofen was incubated with either rat whole liver homogenate, human whole liver homogenate, rat liver mitochondria, or rat liver microsomes, and the formation of ibuprofenyl-CoA measured [10].
• 1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calculated [11].
• (S)- and (R)-ibuprofen were equal in their inhibitory/activating effects on cytokine production, with the exception of stronger IL-8 induction in endothelial cells by (R)-ibuprofen as compared to its chiral analogue [12].
• Twelve hours after the last dose the mean serum level was about 20 micromol/l. Ibuprofen concentrations fluctuated far less in synovial fluid than in serum [13].

Associations of l-Ibuprofen with other chemical compounds

• 5. Clofibric acid added to hepatocyte suspensions transiently increased intracellular concentrations of coenzyme A whereas (R)-ibuprofen transiently decreased CoA concentrations [11].

Gene context of l-Ibuprofen

• AIMS: To study the effect of CYP2C8*3, the most common CYP2C8 variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C8*3 with variant CYP2C9 alleles [6].
• The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects [6].

Analytical, diagnostic and therapeutic context of l-Ibuprofen

• RESULTS: The mean Cmax for (S)- and (R)-ibuprofen decreased with increased particle size of the drug or microspheres in the suspension dosage forms, while the Tmax increased with increased particle size [14].

References