Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug–drug interactions mediated by organic anion transporter 3

Abstract

Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyse the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. The impact of PPIs on the plasma MTX concentration on 73 cycles of HD-MTX therapy was analysed retrospectively in 43 patients. Also investigated was the involvement of OAT3 in PPI-MTX drug interaction in an in vitro study using human OAT3 expressing HEK293 cells. In a retrospective study, patients who received a PPI had significantly higher MTX levels at 48 h (0.38 vs. 0.15 μmol l , respectively, p = 0.000018) and 72 h (0.13 vs. 0.05 μmol l , respectively, p = 0.0002) compared with patients who did not receive a PPI (but received famotidine). Moreover, in vitro experiments demonstrated that PPIs (esomeprazole, lansoprazole, omeprazole and rabeprazole) inhibited hOAT3-mediated uptake of MTX in a concentration-dependent manner (IC values of 0.40-5.5 μ m), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3-mediated MTX uptake. These results demonstrated that co-administration of PPI, but not famotidine, could result in a pharmacokinetic interaction that increases the plasma MTX levels, at least in part, via hOAT3 inhibition.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

“…Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate more strongly than the corresponding (R)-lansoprazole (Table 2). The inhibitory effect of (S)-lansoprazole against hOAT3-mediated transport of pemetrexed and methotrexate was comparable to the results in the several previous reports with racemic lansoprazole [11, 15, 36]. In contrast, the inhibitory effect against hOAT1 did not show stereoselectivity (Table 1).…”

“…In contrast, the ratio of unbound C max to IC 50 value of (S)-lansoprazole against hOAT3 in PM of CYP2C19 was ≥0.1, suggesting a clinical interaction between (S)-lansoprazole and hOAT3 substrates in PM (data not shown). Indeed, the delayed elimination of methotrexate (hOAT3 substrate) was observed in patients receiving racemic lansoprazole [12-14, 36]. Miura et al [38] demonstrated that the pharmacokinetics of (S)-lansoprazole were more intensely affected by ­ CYP2C19 polymorphism than those of (R)-lansoprazole, suggesting that (S)-lansoprazole is responsible for individual variations of lansoprazole-induced drug interactions associated with hOAT3.…”

Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

“…Around 80% of MTX is primarily excreted via the kidney in its unchanged form with transporter-mediated secretion prevailing over glomerular filtration. Notably, case reports of life-threatening kidney failure were reported after coadministration of MTX with probenecid, NSAIDs, or proton pump inhibitors, which supports an involvement of the OATs in tubular handling of MTX [111][112][113][114].…”

Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder

“…However, the impact of efflux transporter (OAT3) inhibition in renal tubules and/or in the blood brain barrier deserves an investigation [for a review on OAT family, ( 36 , 37 )]. Several compounds such as probenecid and proton pump inhibitors have been described to inhibit OAT3 transport which increases plasma and brain concentrations ( 38 , 39 ). It could be of interest to combine baclofen with an OAT3 inhibitor to investigate if brain and plasma concentrations are increased and if it is associated with an improvement of the clinical effect.…”