Stereoselective binding of etodolac to human serum albumin

Muller, Noëlle; Lapicque, Françoise; Monot, C.; Payan, E.; Dropsy, R.; Netter, Patrick

doi:10.1002/chir.530040407

Cited by 15 publications

(5 citation statements)

References 26 publications

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“…In a study involving the binding of etodolac enantiomers to human serum albumin, Muller et al (1992) found a different extent of binding than that earlier reported by in human plasma (table III). As was recognised by Muller et al (1992), plasma contains many endogenous components that might cause the binding in plasma to differ from that seen in a solution of albumin.…”

Section: Protein Bindingcontrasting

confidence: 62%

“…As was recognised by Muller et al (1992), plasma contains many endogenous components that might cause the binding in plasma to differ from that seen in a solution of albumin. Furthermore, Muller et al (1992) used individual enantiomers to assess the extent of binding, whereas spiked their plasma samples with racemate. Nevertheless, a higher binding of the R-enantiomer, as reported earlier , is quite consistent with the lower CL and Vd of R-than S-etodolac.…”

Section: Protein Bindingmentioning

confidence: 97%

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Etodolac Clinical Pharmacokinetics

Brocks

Jamali

1994

Clinical Pharmacokinetics

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Etodolac is a chiral nonsteroidal anti-inflammatory drug (NSAID) that is marked as the racemate. Currently, the drug is available in several countries for the treatment of arthritis and the alleviation of pain. Etodolac possesses several unique disposition features mainly due to its stereoselective pharmacokinetics. In plasma, the concentrations of the 'inactive' R-enantiomer are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. In common with other NSAIDs, the drug is highly plasma protein bound, and undergoes virtually complete biotransformation to oxidised metabolites and acyl-glucuronides. Etodolac is well absorbed, with maximal plasma concentrations attained within 1 to 2 hours in healthy volunteers. The area under the plasma concentration-time curve of racemic etodolac increases linearly with doses used clinically. The elimination half-life of etodolac is between 6 and 8 hours in plasma, and is similar for both enantiomers. The volume of distribution (Vd) of racemic etodolac is higher than that of most other NSAIDs mainly because of the extensive distribution of the S-enantiomer. The very large Vd of the S-enantiomer, compared with its antipode is, at least in part, due to its less extensive plasma protein binding. In addition to the unchanged drug, substantial concentrations of the acyl-glucuronides of etodolac are found in both plasma and the synovial fluid of patients with arthritis. A limited amount of conjugated etodolac is found in the bile of patients following cholecystectomy. Hepatic cirrhosis has no effect on the pharmacokinetics of racemic etodolac, although the effect of hepatic dysfunction on the pharmacokinetics of the individual enantiomers has yet to be determined. In elderly non-arthritic individuals with excellent kidney function, aging does not affect the pharmacokinetics of etodolac. The pharmacokinetics of the drug in patients with renal failure have not been published, and may be important because the acyl-glucuronides are renally cleared.

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Section: Protein Bindingcontrasting

confidence: 62%

Section: Protein Bindingmentioning

confidence: 97%

Etodolac Clinical Pharmacokinetics

Brocks

Jamali

1994

Clinical Pharmacokinetics

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“…It can be deduced from equilibrium dialysis experiments concerning each enantiomer separately, in a I giL HSA solution, at the lowest drug concentrations (drug: protein ratio < I), that the R form is more bound than its antipode. Inverse results were observed at the highest drug concentrations (Muller et al 1992). For higher albumin concentrations (40 giL), S was bound in a larger extent than R in a wide drug concentration range (2 to 800 mg/L).…”

Section: Etodolacmentioning

confidence: 67%

“…Etodolac was studied by spectrofluorimetry (I giL HSA) [Muller et al 1992]: the 2 enantiomers were shown to displace dansylamide from its binding site, while dansylsarcosin was shown to be displaced extensively only by the S enantiomer. This indicates that the S form is bound to the 2 sites, I and II, but that its antipode is pr~ferentially bound to site I.…”

Section: Etodolacmentioning

confidence: 99%

Protein Binding and Stereoselectivity of Nonsteroidal Anti-Inflammatory Drugs

Lapicque¹,

Muller²,

Payan³

et al. 1993

Clinical Pharmacokinetics

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Stereoselective binding of nonsteroidal anti-inflammatory drugs (NSAIDs) can be studied using various techniques. Thus the results obtained by different investigators may be poorly consistent and even contradictory. NSAIDs are bound stereoselectively to serum albumin to different degrees depending on the drug investigated (ibuprofen, indoprofen, carprofen, etodolac, ketoprofen and flurbiprofen). For other drugs, both enantiomers are bound to a similar extent (pirprofen, fenoprofen). This stereoselectivity could vary with experimental conditions, in particular with protein concentration (ketoprofen, etodolac), leading to individual differences. Finally, the stereoselectivity of protein binding and of pharmacokinetics can be compared: differences in binding between enantiomers can explain their differences in pharmacokinetics, once metabolic properties such as inversion have been taken into account.

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“…This data predicts that S-etodolac binds Fzd 8 slightly better than R-; R-etodolac binds Fzd 7 slightly better than S-; and both have equal predicted binding affinity for Fzd 4. Etodolac enantiomers show stereoselective binding to human serum albumin [ 19 ] and have enantioselective pharmacokinetics. However, it is currently unclear how these predicted Fzd receptor affinity differences of R- and S-etodolac may affect Wnt signaling inhibition; thus further investigation is needed to determine the specific binding affinities of etodolac enantiomers to different FZD receptors and elucidate the biological impact of the subtle predicted differences.…”

Section: Resultsmentioning

confidence: 99%