Thiopurine S-methyltransferase as a target for drug interactions.
OBJECTIVE
The present study was undertaken to investigate the possible effects of various agents on thiopurine methyltransferase (TPMT) activity in red blood cells (RBCs) from patients with chronic inflammatory bowel disease (IBD).


METHODS
In three groups of patients with very high, normal and intermediate TPMT activity (each n=6), the inhibitory potential of furosemide, piretanide, azathioprine (AZA) and testosterone was assessed by ex vivo measurements of TPMT activity in RBCs. From individual concentration-response curves, IC50 values have been determined.


RESULTS
Independent of the basal TPMT activity, lowest IC50 values were calculated for furosemide (15-19 microM), followed by testosterone (30-72 microM), piretanide (300-313 microM) and AZA (430-532 microM). Compared with reported plasma concentration achieved during treatment, only furosemide would have the potential to inhibit TPMT also in vivo, whereas the IC50 values of the other agents are far above the corresponding plasma levels.


CONCLUSIONS
Our ex vivo study revealed that only furosemide has the potential to inhibit TPMT activity in patients with IBD. This possibility should be taken into consideration if the diuretic and AZA or 6-mercaptopurine are coadministered. However, the extrapolation to the clinical setting remains open.
Xin
Hua-Wen
HW
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376, Stuttgart, Germany.
Fischer
Christine
C
Schwab
Matthias
M
Klotz
Ulrich
U
D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000494:pharmacology; D002648:Child; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005665:Furosemide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000097:blood; D020128:Inhibitory Concentration 50; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged
D004232:Diuretics; D007166:Immunosuppressive Agents; D005665:Furosemide; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine