Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel d-phenylalanine-derivative hypoglycemic agent

Takesada, Hiroko; Matsuda, Keizo; Ohtake, Ryoko; Mihara, Ryuichi; Ono, Ichiro; Tanaka, Kenzö; M, Naito; Yatagai, Masanobu; Suzuki, Eiichiro

doi:10.1016/0968-0896(96)00187-3

Cited by 28 publications

(14 citation statements)

References 10 publications

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“…5 The primary metabolites are considerably less potent than the parent and are mainly the products of oxidative metabolism. Previous studies into CYP450 enzymes suggest the involvement of the isoenzymes CYP2C9 and CYP3A4 in nateglinide metabolism (approximately 70% and 30% of total metabolism, respectively).…”

mentioning

confidence: 99%

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

Anderson¹,

Shelley²,

Crick³

et al. 2002

The Journal of Clinical Pharma

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The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two-group, two-way crossover, open-label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7- to 14-day washout, received both warfarin and nateglinide (120 mgnateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R- and S-enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.

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mentioning

confidence: 99%

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

Anderson¹,

Shelley²,

Crick³

et al. 2002

The Journal of Clinical Pharma

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“…CYP2C9 and CYP3A4 have been suggested to take part in the metabolism of nateglinide, with CYP2C9 metabolizing it to a much greater extent than CYP3A4 [2,3]. The biotransformation of nateglinide yields several metabolites, of which the dehydrogenated M7 metabolite seems to be as potent a blood glucose-lowering agent as the parent nateglinide [20]. However all other metabolites appear to be much less active [20].…”

Section: Discussionmentioning

confidence: 99%

“…The biotransformation of nateglinide yields several metabolites, of which the dehydrogenated M7 metabolite seems to be as potent a blood glucose-lowering agent as the parent nateglinide [20]. However all other metabolites appear to be much less active [20]. Total exposure to M7 is about 5% of that of nateglinide [2].…”

Section: Discussionmentioning

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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“…5). 9 When the L-enantiomer was administered to rats, L-M1 (diastereomer of M1) and L-M2 (diastereomer of M2) were found as major metabolites. The cumulative excretion of M1 of nateglinide into bile in control rats was higher than that in GK rats, although the difference was not significant (Fig.…”

Section: Cumulative Excretion Of Nateglinide Its L-enantiomer and Thmentioning

confidence: 99%

“…9 Bezafibrate and 3-(4-chlorophenoxy) propionic acid were purchased from Wako Pure Chemical Industries (Tokyo, Japan). Fenofibrate was purchased from SigmaAldrich Japan Inc (Tokyo, Japan).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats, a model for type 2 diabetes mellitus

et al. 2009

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The pharmacokinetics of (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) and its enantiomer (L-enantiomer) was studied in Goto-Kakizaki (GK) rats after intravenous administration of nateglinide or L-enantiomer at a dose of 40 micromol/kg body weight. Nateglinide, its L-enantiomer and their metabolites in serum, bile and urine were determined. The total clearance (CL(tot)) and the volume of distribution (Vd) was slightly higher for nateglinide than those for L-enantiomer in control rats, although the differences were not statistically significant. The cumulative excretions of L-M1 (major metabolite of L-enantiomer) and L-M2 (major metabolite of L-enantiomer) into bile were almost the same as that of M1 (major metabolite of nateglinide)and M2 (major metabolite of nateglinide). In GK rats, CL(tot) and Vd were higher for nateglinide than those for L-enantiomer. The cumulative excretion of L-M1 and L-M2 were not different from those of M1 and M2, respectively, into bile or urine. CL(tot) and Vd for nateglinide or L-enantiomer in GK rats were not different from those in control rats. The total excretion of M1, M2, L-M1, and L-M2 into bile or urine in GK rats was not substantially different from that of control rats. These results suggest that the L-enantiomer of nateglinide shows higher CL(tot) and Vd compared with nateglinide, especially in the diabetic state.

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Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel d-phenylalanine-derivative hypoglycemic agent

Cited by 28 publications

References 10 publications

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers

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

Pharmacokinetics of nateglinide enantiomers and their metabolites in Goto‐Kakizaki rats, a model for type 2 diabetes mellitus

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