Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers

Avgerinos, A.; Hutt, Andrew J.

doi:10.1002/chir.530020410

Cited by 35 publications

(16 citation statements)

References 35 publications

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“…Nevertheless, it should be kept in mind that the unidirectional conversion of R-(Ϫ)-ibuprofen to S-(ϩ)-ibuprofen occurs in vivo (2,16). The apparent oral clearance of S-(ϩ)-ibuprofen was approximately halved in carriers of the CYP2C9*3/*3 genotype, an effect that is similar in magnitude to those found with voriconazole or fluconazole in the present study.…”

Section: Discussionsupporting

confidence: 83%

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S -(+)- and R -(−)-Ibuprofen

Hynninen

Olkkola

Leino

et al. 2006

Antimicrob Agents Chemother

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Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(؉)-and R-(؊)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(؉)-and R-(؊)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(؉)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C max ) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t 1/2 ) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(؉)-ibuprofen was 183% of the control value (P < 0.001) and its mean C max was 116% of the control value (P < 0. Voriconazole is a novel triazole antifungal agent, available as oral and intravenous formulations, with potent activity against a broad spectrum of clinically significant pathogens, including Aspergillus, Cryptococcus, and Candida species (5,8,27). Voriconazole is metabolized by the cytochrome P450 (CYP) enzyme system, mainly by the polymorphic enzyme CYP2C19 and to a lesser extent by the polymorphic enzymes CYP2C9 and CYP3A4 (13; G. Mikus, M. Drzevinska, V. Schoevel, J. Burhenne, K. D. Riedel, T. Thomsen, M. M. Hoffmann, J. Weis, J. Rengelshausen, and W. E. Haefeli, Abstr. 7th Congr. Eur. Assoc. Clin. Pharmacol. Ther., abstr. 418, 2005). In vivo studies have shown that addition of voriconazole at 300 mg twice daily to a 30-mg oral dose of warfarin in healthy volunteers resulted in a doubling of the prothrombin time from 8.4 to 16.6 s (28), probably due to inhibition of CYP2C9. In addition, coadministration of voriconazole has significantly increased the area under the plasma concentration-time curve (AUC) of phenytoin, a substrate of CYP2C9 (30); the AUC of omeprazole, a substrate of CYP2C19 (http://www.emea.eu .int./humandocs/Humans/EPAR/vfend/vfend.htm); and the AUC of cyclosporine, which is metabolized by CYP3A4 (31).Fluconazole is another azole antifungal agent and a welldocumented potent inhibitor of CYP2C9-catalyzed reactions both in vitro (3,20) and in vivo (4, 18) and a weaker inhibitor of CYP3A4-catalyzed reactions (23). It has also been found to inhibit CYP2C19-catalyzed reactions both in vitro (34) and in vivo (17). However, there are few data on the possible interactions between fluconazole and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatment with fluconazole significantly increased the AUC of the CYP2C9 substrate celecoxib (7), and recently, it has been shown that coadministration of fluconazole and a novel cyclooxygenase 2 (COX-2)-selective inhibitor,...

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Section: Discussionsupporting

confidence: 83%

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S -(+)- and R -(−)-Ibuprofen

Hynninen

Olkkola

Leino

et al. 2006

Antimicrob Agents Chemother

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“…The linear relationship between AUC~-values and dose for dexibuprofen administered alone is in line with published results [9,16,17], although the latter were obtained with dexibuprofen as part of R, S-ibuprofen. In our case, the dose-normalised AUC~ of dexibuprofen from R, S-ibuprofen showed a small but statistically significant tendency, to decrease with increasing dose.…”

Section: Discussionsupporting

confidence: 80%

“…Second, AUC~-values from Study 2 agreed with the corresponding data from Study 1 for the 400 mg Table 2, compared favourably with data from the literature [3,4,9,11,12,16,17]. This confirms that, at least for dexibuprofen and over the dose-range investigated, there was no major difference between pharmacokinetic parameters of the drug administered alone or as part of the racemate.…”

Section: Discussionsupporting

confidence: 76%

“…An explanation for this possible difference in pharmacokinetic behaviour between dexibuprofen administered alone or as part of R, S-ibuprofen could be the presence of the R(-)-enantiomer, which clearly displayed a non-linear relationship between dosenormalised AUC~-values and dose, confirming a previous report [16,17]. Like other non-steroidal antiinflammatory drugs, the enantiomers of R, Sibuprofen are extensively bound to plasma albumin.…”

Section: Discussionsupporting

confidence: 70%

“…Like other non-steroidal antiinflammatory drugs, the enantiomers of R, Sibuprofen are extensively bound to plasma albumin. Recent experiments [16,17] have revealed that each enantiomer displayed concentration-dependent protein binding over a wide range of dosages (200 to 1200 rag, single administration). However, the non-linearity of plasma protein binding was found to be significant only for the R-enantiomer and not for dexibuprofen, thus providing at least one explanation for the non-linear relationship between AUC= and dose displayed by both the R-enantiomer [this study] and R, S-ibuprofen [12,18].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen

Gabard

Nirnberger²,

Schiel³

et al. 1995

Eur J Clin Pharmacol

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Two bioavailability studies of S(+)-ibuprofen (dexibuprofen) were conducted in healthy volunteers to define the relationship between the bioavailability of the drug after administration of dexibuprofen alone or as part of ibuprofen racemate. Enantioselective plasma drug analysis was used throughout. In the first study, the bioavailability of dexibuprofen from a 400 mg tablet formulation was compared with that from 400 mg in aqueous solution. The tablet formulation did not influence the bioavailability of the drug and dexibuprofen was well absorbed from the gastro-intestinal tract. The second study was divided into three identical parts. Bioavailability of dexibuprofen 200, 400 and 600 mg was compared with its bioavailability from ibuprofen racemate 400, 800 and 1200 mg. The second study showed that the mean relative bioavailability of dexibuprofen to ibuprofen racemate was 0.66, thus enabling the estimation of clinically useful dexibuprofen doses from the usual doses of the racemate. The 95% confidence interval limits did not include 0.5, leading to the conclusion that administering half of the racemate dose would not provide patients with an adequate amount of therapeutically active drug.

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Gastrointestinal Adverse Reactions from Ibuprofen

Rainsford

Bjarnason

2015

Ibuprofen

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Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers

Cited by 35 publications

References 35 publications

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S -(+)- and R -(−)-Ibuprofen

Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S -(+)- and R -(−)-Ibuprofen

Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen

Gastrointestinal Adverse Reactions from Ibuprofen

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