Effects of methimazole on the elimination of irinotecan.
OBJECTIVE
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.
van der Bol
Jessica M
JM
Department of Medical Oncology, Erasmus MC University Hospital, Daniel den Hoed Cancer Center, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Visser
Theo J
TJ
Loos
Walter J
WJ
de Jong
Floris A
FA
Wiemer
Erik A C
EA
van Aken
Maarten O
MO
Planting
Andre S
AS
Schellens
Jan H
JH
Verweij
Jaap
J
Mathijssen
Ron H J
RH
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013956:Antithyroid Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism; D006111:Graves Disease / Q000150:complications / Q000188:drug therapy; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008713:Methimazole / Q000494:pharmacology*; D008875:Middle Aged; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D013956:Antithyroid Agents; D002166:Camptothecin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008713:Methimazole; D000099148:UGT1A1 Enzyme