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The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction

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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.

1 The presence of inhibitors of drug e ux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was con®rmed based on the uptake of [ 3 H]-vinblastine (VBL) by Caco-2 cells. 2 The uptake of [ 3 H]-VBL by Caco-2 cells was signi®cantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [ 3 H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3 These results show that the major inhibitor of e ux transport of VBL is di erent from that of CYP3A4. 4 Further separation of the 60% methanol eluate a orded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [ 3 H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [ 3 H]-VBL by Caco-2 cells. 5 The order of inhibitory potency of these compounds was FC7264DHBG4bergamottin4ber-gapten4bergaptol. While, the IC 50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and 420 mM, respectively. Bergaptol speci®cally inhibited VBL e ux. 6 DHBG was thus identi®ed as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7 Therefore, the inhibition of e ux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

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Model analysis based on receptor occupancy indicates that H1 receptor blockade is the primary cause of antipsychotics-induced weight gain and diabetes mellitus.

The use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.