Absorption, metabolism and excretion of a single oral dose of 14 C-repaglinide during repaglinide multiple dosing

Heiningen, P. N. M. Van; Hatorp, Vibeke; Nielsen, Kristina Tomra; Hansen, Kristian T.; Lier, Jan Jaap van; Merbel, N. C. De; Oosterhuis, B.; Jonkman, J. H. G.

doi:10.1007/s002280050667

Cited by 75 publications

(65 citation statements)

References 4 publications

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“…Repaglinide metabolism is complex, and six different metabolites have been reported ( Fig. 1) (van Heiningen et al, 1999;Bidstrup et al, 2003). The metabolites have no hypoglycemic effect and are mainly excreted via bile into feces (van Heiningen et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…1) (van Heiningen et al, 1999;Bidstrup et al, 2003). The metabolites have no hypoglycemic effect and are mainly excreted via bile into feces (van Heiningen et al, 1999). Involvement of CYP2C8 and CYP3A4 has been reported in vitro, as well as in vivo (Bidstrup et al, 2003;Niemi et al, 2003Niemi et al, , 2004Kajosaari et al, 2005), but the relative contribution of the two enzymes remains unclear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

Säll

Houston²,

Galetin

2012

Drug Metab Dispos

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ABSTRACT:Repaglinide is presently recommended by the U.S. Food and Drug Administration as a clinical CYP2C8 probe, yet current in vitro and clinical data are inconsistent concerning the role of this enzyme in repaglinide elimination. The aim of the current study was to perform a comprehensive investigation of repaglinide metabolic pathways and assess their contribution to the overall clearance. Formation of four repaglinide metabolites was characterized using in vitro systems with differential complexity. Full kinetic profiles for the formation of M1, M2, M4, and repaglinide glucuronide were obtained in pooled cryopreserved human hepatocytes, human liver microsomes, human S9 fractions, and recombinant cytochrome P450 enzymes. Distinct differences in clearance ratios were observed between CYP3A4 and CYP2C8 for M1 and M4 formation, resulting in a 60-fold M1/M4 ratio in recombinant (r) CYP3A4, in contrast to 0.05 in rCYP2C8. Unbound K m values were within 2-fold for each metabolite across all in vitro systems investigated. A major system difference was seen in clearances for the formation of M2, which is suggested to be a main metabolite of repaglinide in vivo. An approximately 7-fold higher unbound intrinsic clearance was observed in hepatocytes and S9 fractions in comparison to microsomes; the involvement of aldehyde dehydrogenase in M2 formation was shown for the first time. This systematic analysis revealed a comparable in vitro contribution from CYP2C8 and CYP3A4 to the metabolism of repaglinide (<50%), whereas the contribution of glucuronidation ranged from 2 to 20%, depending on the in vitro system used. The repaglinide M4 metabolic pathway is proposed as a specific CYP2C8 probe for the assessment of drug-drug interactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

Säll

Houston²,

Galetin

2012

Drug Metab Dispos

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“…After oral administration it is rapidly absorbed with absolute bioavailability of approximately 60% (Hatorp, 2002). Repaglinide is extensively biotransformed in the liver to inactive metabolites, which are predominantly excreted via the feces and to approximately 8% via urine (van Heiningen et al, 1999). In vitro, both CYP3A4 and CYP2C8 were shown to be the crucial enzymes responsible for repaglinide metabolism with formation of M1 and M4 as the quantitatively most important metabolites.…”

Section: Introductionmentioning

confidence: 99%

Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

et al. 2011

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ABSTRACT:The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n ‫؍‬ 4), CYP2C8*1/*3 (n ‫؍‬ 13), or CYP2C8*1/*1 (n ‫؍‬ 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve . In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C max of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.

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“…Among this CYP3A4 has been identified as an important enzyme in the in-vitro metabolism of repaglinide [23]. The repaglinide pharmacokinetics was further complicated because of active hepatic uptake of repaglinide by OATP uptake transporter and it is a substrate for the OATP transporter [24].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

Goud¹,

Maddi²,

Devanna³

et al. 2016

ADMET DMPK

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Absorption, metabolism and excretion of a single oral dose of 14 C-repaglinide during repaglinide multiple dosing

Cited by 75 publications

References 4 publications

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

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