Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy.
OBJECTIVE
To assess whether or not co-administration of proton pump inhibitors (PPIs) is a risk factor for delayed elimination of plasma methotrexate (MTX) in high-dose MTX (HDMTX) therapy for malignant diseases.


METHODS
To assess the effects of PPI co-administration on elimination of plasma MTX, we examined plasma MTX concentration data on 171 cycles of HDMTX therapy performed in 74 patients. We performed multiple logistic regression analysis to evaluate PPI co-administration as a risk factor. Inhibitory potencies of omeprazole, lansoprazole, rabeprazole and pantoprazole on MTX transport via breast cancer resistance protein (BCRP, ABCG2) were also investigated in an in vitro study using membrane vesicles expressing human BCRP.


RESULTS
We identified co-administration of PPIs as a risk factor for delayed elimination (odds ratio 2.65, 95% confidence interval 1.03, 6.82) as well as renal and liver dysfunction. All four PPIs inhibited BCRP-mediated transport of MTX, with half-maximal inhibitory concentrations of 5.5-17.6 microM--considerably higher than the unbound plasma concentrations of the PPIs.


CONCLUSIONS
Our results support previous findings suggesting that PPI co-administration is associated with delayed elimination of plasma MTX in patients with HDMTX therapy. This drug interaction, however, cannot be explained solely by the inhibitory effects of PPIs on BCRP-mediated MTX transport.
Suzuki
Kunihiro
K
Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
Doki
Kosuke
K
Homma
Masato
M
Tamaki
Hirofumi
H
Hori
Satoko
S
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
Kohda
Yukinao
Y
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D054328:Proton Pump Inhibitors; D008727:Methotrexate