Effects of methimazole on the elimination of irinotecan

Abstract

Purpose: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole.

Methods: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole).

Results: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen.

Conclusions: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity.

Fig. 1

Pharmacokinetics of irinotecan and metabolites. a Irinotecan is converted into its 1,000 times more active metabolite SN-38 by carboxylesterases (CES), which are predominately found in the liver. The affinity for this reaction is low, since only a fraction of irinotecan is directly converted into SN-38. Competing with the formation of SN-38 is the CYP3A-mediated inactivation of irinotecan into the metabolites APC and NPC. In turn, carboxylesterases also have the ability to convert both of these compounds into SN-38. SN-38 is glucuronidated by UGT1A into its inactive metabolite SN-38G. In the intestines, β-glucuronidase-producing bacteria can reverse this latter reaction, and thus reactivate SN-38, which causes the dose-limiting toxicity diarrhea. Area under the plasma concentration versus time curves for irinotecan (b), NPC (c), APC (d), SN-38 (e), and SN-38G (f) during all four chemotherapy courses. The open and closed symbols describe the two courses with methimazole and the two courses without methimazole co-treatment, respectively

Fig. 2

In vitro experiments. a Effects of methimazole (striped bars) and fluconazole (open bars) on the formation of NPC, APC, and SN-38 during co-incubation with irinotecan, and effects of methimazole (striped bars) and ketoconazole (open bars) on the formation of SN38G during co-incubation with SN-38. The black bars represent the formation of irinotecan metabolites in the absence of any (potential) inhibitor. b Methimazole induces UGT1A1 mRNA levels. HCT116 cells were cultured in the presence or absence (control) of various concentrations of methimazole. At 5 (cross-hatched bar), 24 (hatched bar) and 48 (white bar) hours total RNA was isolated and used to measure UGT1A1 mRNA levels by quantitative RT-PCR (Taqman™). Depicted is the expression of UGT1A1 compared to the control UGT1A1 levels (black bar), which are arbitrarily set at 1. Error bars indicate 2 × standard deviation (n = 3)