WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Co‐administration of proton pump inhibitors (PPIs) increases plasma methotrexate (MTX) concentration in cancer patients receiving high‐dose MTX (HDMTX) therapy. • There is controversy as to whether or not co‐administration of PPIs affects plasma MTX elimination in HDMTX therapy. • Inhibitory activity of PPIs on breast cancer resistance protein (BCRP) is a possible mechanism for the drug interaction between MTX and PPIs. WHAT THIS STUDY ADDS • Co‐administration of a PPI (omeprazole, lansoprazole, or rabeprazole) was more frequently observed in the delayed MTX elimination group than in the normal MTX elimination group. • Multiple logistic regression analysis with adjustment for significant covariates revealed that PPI co‐administration was a significant risk factor for delayed plasma MTX elimination. • The half‐maximal inhibitory concentration of each PPI in inhibiting BCRP function was much higher than the therapeutic unbound concentration in the plasma. AIM 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 µM – 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.
Ribavirin-induced hemolytic anemia is one cause for cessation of combination therapy with alpha interferon 2b and ribavirin for hepatitis C infection. Determining cellular ribavirin levels in blood, including the levels of its phosphorylated metabolites, might be useful for predicting ribavirin-induced anemia, because the metabolites accumulate in erythrocytes. We simplified an assay method developed previously to make it suitable for routine monitoring of cellular ribavirin. Whole blood diluted with a sixfold volume of ice-cold distilled water was subjected to acid phosphatase digestion to convert phosphorylated ribavirin metabolites to free ribavirin. The resulting mixture, spiked with an internal standard, was treated by phenyl boronic acid column extraction, followed by reverse-phase high-performance liquid chromatography analysis. The calibration curve for ribavirin levels in whole blood was linear at concentrations of 5.3 to 1,024 M (r 2 ؍ 0.9999). Validation coefficients of variation for intra-and interday assays were 2.9 to 5.8% and 4.3 to 8.3%, respectively. We tested this method by monitoring blood ribavirin concentrations in two hepatitis C patients receiving alpha interferon 2b-plusribavirin combination therapy.Ribavirin, a guanosine analog broad-spectrum antiviral agent, is used for hepatitis C virus (HCV) elimination in combination with alpha interferon 2b (2, 3, 13). Polyethyleneglycolalpha interferon 2a combined with oral ribavirin also brings substantial benefit to HCV patients (12,14). Despite the strong beneficial effects of these combination therapies in severe HCV infection, loss of hemoglobin occurs in a substantial population of HCV patients. Progressive loss of hemoglobin leads to anemia, which is counteracted by reducing the ribavirin dose or prematurely discontinuing the combination therapy (1,5,12). Current studies suggest that the excessive accumulation of ribavirin in erythrocytes is responsible for the anemia (8, 11). Once incorporated into erythrocytes, ribavirin is converted into phosphorylated metabolites by intracellular phosphorylation (9). The phosphorylated metabolites decrease intracellular ATP levels, resulting in the reduction of erythrocyte integrity, which is followed by extravascular hemolysis via the reticuloendothelial system (4). It should therefore be possible to predict the occurrence of ribavirin-induced anemia by determining the ribavirin concentrations in blood cells and plasma.A high-performance liquid chromatography (HPLC) method was previously developed to determine ribavirin levels in order to assess the disposition of ribavirin in erythrocytes (7). Since phosphorylated metabolites are the main form of intracellular ribavirin (7, 8), whole-blood samples were treated with acid phosphatase prior to column extraction and analysis. However, the dephosphorylation procedure used in a previous study (7) was too tedious to use for routine monitoring of cellular ribavirin. In the present study, we simplified the dephosphorylation procedure. The modified method was ...
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