Letters

Thiazolidinediones for type 2 diabetes

BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7280.235 (Published 27 January 2001) Cite this as: BMJ 2001;322:235

No evidence exists that pioglitazone induces hepatic cytochrome P450 isoform CYP3A4

  1. N Bradly Glazer (bglazer{at}takedapharm.com), manager, scientific communications,
  2. Wayman Wendell Cheatham, vice president, medical and regulatory
  1. Takeda Pharmaceuticals America, 475 Half Day Road, Suite 500, Lincolnshire, IL 60069, USA
  2. Clinical Research and Development and Medical Affairs UK, SmithKlineBeecham Pharmaceuticals, Mundells, Welwyn Garden City, Hertfordshire AL7 1EY

    EDITOR—In their editorial on thiazolidinediones for type 2 diabetes Krentz et al incorrectly stated: “Pioglitazone induces cytochrome P450 isoform CYP3A4, raising the possibility of drug interactions, such as with oral contraceptives.”1 No supporting documentation was provided for this statement.

    Ishida et al recently evaluated the relation between the therapeutic effects of troglitazone and pioglitazone in steroid induced diabetes.2 Urinary excretion of 6β-hydroxycortisol and the ratio of 6β-hydroxycortisol to cortisol were measured as a marker of CYP3A4 induction. Urinary excretion of 6β-hydroxycortisol was significantly increased with treatment with troglitazone but remained unchanged with treatment with pioglitazone.

    The elimination half life and plasma concentration of prednisolone were also measured.2 Treatment with troglitazone significantly reduced the half life and plasma concentration of prednisolone (by about half); no change was seen with pioglitazone. The results of this study indicated that while both drugs were effective in controlling steroid induced hyperglycaemia, pioglitazone improved glycaemic control without modification of the steroid metabolism by the liver.

    At Takeda Pharmaceuticals we have completed a clinical study (data on file, Takeda Europe, Research and Development Centre) in which we investigated the 6β-hydroxycortisol:free cortisol urinary ratio, commonly used as a specific marker of CYP3A4 induction.3 Six healthy subjects received pioglitazone 45 mg once daily on day 1 and from day 3 to day 12. Among other variables the 6β-hydroxycortisol:free cortisol ratio in urine was evaluated on day 1 and day 12. The mean (SD) 6β-hydroxycortisol:cortisol ratios in day 1 urine samples (n=17) and day 12 urine samples (n=18) were 4.99 (1.92) and 5.11 (2.01) respectively, indicating no difference in the ratio between day 12 and day 1 (P=0.29). These results clearly show that pioglitazone does not induce the hepatic CYP3A4 enzyme system.

    Isoforms contributing to the metabolism of pioglitazone include CYP 2C8 (39%), CYP3A4 (17%), and several other isoforms infrequently used in the known metabolism of other pharmaceutical agents (CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP2D6)4 (data on file, Takeda Pharmaceuticals America). Rosiglitazone is predominantly metabolised by CYP2C8, with CYP2C9 and CYP3A4 contributing to a lesser extent.5

    In summary, there is no evidence to date that pioglitazone induces the hepatic cytochrome P450 isoform CYP3A4 system.

    Footnotes

    • Competing interests Takeda distributes pioglitazone.

    References

    1. 1.
    2. 2.
    3. 3.
    4. 4.
    5. 5.

    All glitazones may exacerbate heart failure

    1. Alastair Benbow, medical director,
    2. Murray Stewart (Murray_W_Stewart{at}sbphrd.com), associate director,
    3. Guy Yeoman, assistant director
    1. Takeda Pharmaceuticals America, 475 Half Day Road, Suite 500, Lincolnshire, IL 60069, USA
    2. Clinical Research and Development and Medical Affairs UK, SmithKlineBeecham Pharmaceuticals, Mundells, Welwyn Garden City, Hertfordshire AL7 1EY

      EDITOR—We write in response to the editorial by Krentz et al and wish to highlight several issues that need further clarification.1 Fluid retention is a class effect of the thiazolidinediones (or glitazones). 2 3 All glitazones therefore have the potential to exacerbate heart failure in patients with heart failure. This is not specific to rosiglitazone. The therapeutic indications for the European licence granted to rosiglitazone and pioglitazone are identical. 2 3 These indications do not include combination treatment with insulin for either agent. Additional cardiovascular studies are ongoing for rosiglitazone.

      More than 30 publications on rosiglitazone can be found in peer reviewed journals, in particular publications specific to improved glycaemic control in combination treatment as for licensed indications. 4 5

      Footnotes

      • Competing interests SmithKline Beecham distributes rosiglitazone.

      References

      1. 1.
      2. 2.
      3. 3.
      4. 4.
      5. 5.
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