Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase

Gaut, Zane N.; Baruth, Herman W.; Randall, Lowell O.; Ashley, Constance J.; Paulsrud, John R.

doi:10.1016/s0090-6980(75)80062-1

Cited by 51 publications

(9 citation statements)

References 10 publications

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“…A chiral behavior has been frequently reported for the pharmacological and pharmacokinetic properties of carprofen. For example, only (S)‐carprofen has significant pharmacological activity . The chiral pharmacokinetic behavior has been also well described in different species.…”

Section: Discussionmentioning

confidence: 99%

Enantioselective Inhibition of Carprofen Towards UDP‐glucuronosyltransferase (UGT) 2B7

et al. 2014

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UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism.

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Section: Discussionmentioning

confidence: 99%

Enantioselective Inhibition of Carprofen Towards UDP‐glucuronosyltransferase (UGT) 2B7

et al. 2014

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“…The prof ens contain a single chiral carbon atom and consequently exist as pairs of stereoisomers or enantiomers (Hutt & Caldwell 1984). In the case of ibuprofen, this drug is used clinically in its racemic form even though it is well known that the desired therapeutic properties of ibuprofen reside almost exclusively with the S-enantiomer (Adams et al 1976;Fried et al 1973;Gaut et al 1975).…”

Section: Discussionmentioning

confidence: 99%

Disposition of Ibuprofen in Patients with Liver Cirrhosis

Treiber

Maier³

et al. 1993

Clinical Pharmacokinetics

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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.

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“…the blood of three subjects receiving single 100-mg oral doses of carprofen were greater than unity up to 16 hr after dosing. The mean f SD of the ratios in the early blood samples (0.5,1, and 2 hr) was 1.21 f 0.09, while the mean of the ratios in the later blood samples (4,6,8,12, and 16 hr) was slightly higher (1.48 f 0.17). The blood level fall-off curves for the (S)-(+) and @)-(-I enantiomers were similar in each of the three subjects for the 4-16-hr Deriod.…”

mentioning

confidence: 85%

“…In the rat, the (R)-(-) enantiomer is eliminated from the blood and secreted in the bile as the ester glucuronide at a rate approximately twice that of the (5')-(+) enantiomer. Concurrently, the (S)-(+) isomer, the pharmacologically more active enantiomer (8), persists longer in rat blood. Preliminary data suggested a preferred urinary elimination of the ( S ) -( + ) enantiomer as the ester glucuronide and a preferred fecal elimination of the (R)-(-) enantiomer in humans (7).…”

mentioning

confidence: 96%

High-performance Liquid Chromatographic Determination of Stereoselective Disposition of Carprofen in Humans

Stoltenborg

Puglisi

Rubio

et al. 1981

Journal of Pharmaceutical Sciences

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Stereoisomeric relationships among anti-inflammatory activity, inhibition of platelet aggregation, and inhibition of prostaglandin synthetase

Cited by 51 publications

References 10 publications

Enantioselective Inhibition of Carprofen Towards UDP‐glucuronosyltransferase (UGT) 2B7

Enantioselective Inhibition of Carprofen Towards UDP‐glucuronosyltransferase (UGT) 2B7

Disposition of Ibuprofen in Patients with Liver Cirrhosis

High-performance Liquid Chromatographic Determination of Stereoselective Disposition of Carprofen in Humans

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