Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide

Niemi, Mikko; Neuvonen, Mikko; Juntti‐Patinen, Laura; Backman, Janne T.; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(03)00089-4

Cited by 20 publications

(13 citation statements)

References 26 publications

(41 reference statements)

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“…The apparent formation rate constant (k f ) of M7 remained unchanged following coadministration of gemfibrozil and itraconazole. In contrast, earlier work [21] showed that fluconazole reduces the k f of M7 by 42% (from 3.0 to 1.7 h −1 , P = 0.0033) (Figure 3).…”

Section: Resultscontrasting

confidence: 61%

“…It is eliminated by oxidative biotransformation via CYP2C9 (70% of metabolism) and CYP3A4 (30% of metabolism) and by urinary excretion of unchanged nateglinide (15% of an oral dose) [11, 12]. In a previous investigation, fluconazole, an inhibitor of CYP2C9 [15, 16], CYP2C19 [17] and CYP3A4 [18, 19], raised the plasma concentrations of nateglinide and decreased the formation of its M7 metabolite, indicating that either CYP2C9 or CYP3A4 or both contribute to the biotransformation of nateglinide to M7 in vivo [21], although no direct in vitro evidence is available to support this view. In a genetic association study, the CYP2C9 * 3 allele was associated with a decreased clearance and increased plasma concentrations of nateglinide [26], supporting a significant role for CYP2C9 in its biotransformation in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…To compare the mechanism of the interaction between the gemfibrozil-itraconazole combination and nateglinide, with that between fluconazole and nateglinide, the k f of M7 was also determined for our previous interaction study between fluconazole and nateglinide. Both studies used the same nateglinide dosage and blood sampling protocol up to 7 h [21].…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Niemi

Backman

Juntti‐Patinen

et al. 2005

Brit J Clinical Pharma

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Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, • )] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro , gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. ResultsDuring the gemfibrozil-itraconazole phase, the AUC(0, • ) and C max of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range -8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t max and t 1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.

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Section: Resultscontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Niemi

Backman

Juntti‐Patinen

et al. 2005

Brit J Clinical Pharma

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“…Plasma concentrations of repaglinide and its M1, M2, and M4 metabolites were quantified by use of an API 3000 liquid chromatography‐tandem mass spectrometry (LC/MS/MS) system (Sciex Division of MDS Inc., Toronto, Ontario, Canada) as described previously 42 . Plasma concentrations of nateglinide and its M7 metabolite were quantified by use of a Q Trap LC/MS/MS system (Sciex Division of MDS Inc.) 43 . The limits of quantification were 0.01 ng/mL for repaglinide and 5 ng/mL for nateglinide.…”

Section: Methodsmentioning

confidence: 99%

Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Repaglinide and Nateglinide

Kalliokoski

Neuvonen

et al. 2008

The Journal of Clinical Pharma

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Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 0.5-mg dose of repaglinide and 60-mg dose of nateglinide with a washout period of 1 week. Participants with SLCO1B1 c.521CC genotype (n = 4) had a 59% (P = 0.001) or 72% (P < 0.001) greater mean area under the plasma repaglinide concentration-time curve (AUC(0-infinity)) than participants with c.521TC (n = 12) or c.521TT (n = 16) genotypes. The AUC(0-infinity) of repaglinide metabolites M2 and M4 were 112% (P = 0.004) and 81% (P = 0.002) larger in participants with c.521CC genotype than in those with c.521TT genotype, but no differences existed in the pharmacokinetics of M1. Maximum decrease in blood glucose concentration correlated with repaglinide AUC(0-infinity) (r = 0.412, P = 0.019). SLCO1B1 polymorphism had no significant effect on the pharmacokinetics or pharmacodynamics of nateglinide or its M7 metabolite. Thus, in contrast to repaglinide, the disposition of nateglinide is unaffected by the SLCO1B1 c.521T>C polymorphism.

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“…The elimination half-life ( ) of nateglinide is about 1.5 h. The enzymes involved in its biotransformation have not yet been fully characterized, but cytochromes P450 (CYP) 2C9 and 3A4 contribute to nateglinide metabolism in vitro [2,3]. Fluconazole (400 mg on day 1 and 200 mg on days 2-4), an inhibitor of CYP2C9 [4], CYP2C19 [5] and CYP3A4 [6], increased the AUC(0, • ) of nateglinide by 48% and impaired the formation of the M7 (a dehydro derivative) metabolite of nateglinide [7].…”

Section: Introductionmentioning

confidence: 99%

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects

Niemi

Backman

Neuvonen

et al. 2003

Brit J Clinical Pharma

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Aims Our aim was to investigate the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide, a novel short-acting antidiabetic drug. Methods In a randomized crossover study with two phases, 10 healthy volunteers took 600 mg rifampicin or placebo orally once daily for 5 days. On day 6 of both phases, they ingested a single 60 mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 h postdose. Results Rifampicin decreased the mean AUC(0,7 h) of nateglinide by 24% (range 5-53%; P = 0.0009) and shortened its half-life ( ) from 1.6 to 1.3 h ( P = 0.001). However, the peak plasma nateglinide concentration ( C max ) remained unchanged. The AUC(0,7 h) of the M7 metabolite of nateglinide was decreased by 19% ( P = 0.002) and its was shortened from 2.1 to 1.6 h by rifampicin ( P = 0.008). Rifampicin had no significant effect on the blood glucose-lowering effect of nateglinide. Conclusions Rifampicin modestly decreased the plasma concentrations of nateglinide probably by inducing its oxidative biotransformation. In some patients, rifampicin may reduce the blood glucose-lowering effect of nateglinide.

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Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide

Abstract: Fluconazole raised the plasma concentrations and reduced the systemic elimination of nateglinide probably by inhibiting its cytochrome P4502C9-mediated biotransformation. Concomitant use of fluconazole with nateglinide may prolong its blood glucose-lowering effect.

Cited by 20 publications

References 26 publications

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Repaglinide and Nateglinide

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects

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