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Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide.

Methods

In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h.

Results

During the pioglitazone phase, the mean peak plasma repaglinide concentration (Cmax) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide.

Conclusions

Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.

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Acknowledgements

We would like to thank Mr Jouko Laitila, Mrs Kerttu Mårtensson, Mrs Eija Mäkinen-Pulli, Mr Mikko Neuvonen and Mrs Lisbet Partanen for skilful technical assistance. The authors have identified no conflicts of interest in relation to this manuscript. This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency (Tekes), the Sigrid Juselius Foundation, and the Wilhelm and Else Stockmann Foundation. The experiments comply with the current laws of Finland, and the study protocol was approved by the Ethics Committee for Studies in Healthy Subjects and Primary Care of the Hospital District of Helsinki and Uusimaa and the Finnish National Agency for Medicines.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University, Central Hospital, Helsinki, Finland

    Lauri I. Kajosaari, Tiina Jaakkola, Pertti J. Neuvonen & Janne T. Backman

  2. Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland

    Pertti J. Neuvonen

Authors
  1. Lauri I. Kajosaari
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  2. Tiina Jaakkola
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  3. Pertti J. Neuvonen
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  4. Janne T. Backman
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Correspondence to Pertti J. Neuvonen.

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Kajosaari, L.I., Jaakkola, T., Neuvonen, P.J. et al. Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide. Eur J Clin Pharmacol 62, 217–223 (2006). https://doi.org/10.1007/s00228-005-0093-8

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  • DOI: https://doi.org/10.1007/s00228-005-0093-8

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