Sulfasalazine Inhibits the Absorption of Folates in Ulcerative Colitis

Halsted, Charles H.; Gandhi, Gautam; Tamura, Tsunenobu

doi:10.1056/nejm198112173052506

Cited by 110 publications

(28 citation statements)

References 13 publications

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“…Manifestations of (sub)clinical folate deficiency requiring folate supplementation had been reported previously during SSZ single-drug therapy in patients with RA (17)(18)(19)(20)(21)(22). Thus far, the mechanisms proposed to underlie these effects were inhibitory effects of SSZ on intestinal folate absorption (25)(26)(27) and several enzymes in intracellular folate metabolism (23,24).…”

Section: Discussionmentioning

confidence: 84%

“…With respect to folate absorption, it is important to note that the intestinal folate transporter is structurally and functionally identical to the RFC expressed in CEM cells (62)(63)(64). Thus, original reports of impaired intestinal folate absorption following SSZ treatment (25)(26)(27) can be attributed to direct inhibition of intestinal RFC by SSZ. Complementary inhibitory effects of SSZ on enzymes in folate metabolism (23,24) may then further aggravate the folate-deficient status.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, one notable adverse effect observed was a persistent increase in plasma homocysteine levels in patients with RA who were receiving the combination of MTX and SSZ, compared with those receiving single-drug therapy (15,16). Elevated plasma homocysteine levels are associated with cellular folate depletion (17)(18)(19)(20)(21)(22), which has been ascribed to the inhibitory effects of SSZ on several intracellular enzymes involved in folate metabolism (23,24) and/or inhibition of intestinal folate uptake (25)(26)(27).…”

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confidence: 99%

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Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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“…Although the solubilization status of sulfasalazine in the intestinal fluid may not be precisely predictable, it is likely that its concentration much exceeds its IC 50 (half inhibition concentration) of ϳ60 M, which was determined in the preceding study for hPCFT/HCP1-mediated methotrexate transport (19). Thus the malabsorption of folate by inhibition of its hPCFT/ HCP1-mediated transport may explain the higher risk of folate deficiency reported for patients treated with sulfasalazine (8,9). On the other hand, indomethacin and diclofenac may least likely be involved in folate malabsorption, although they were found to inhibit rPCFT/HCP1-mediated folate transport (Figs.…”

Section: Discussionmentioning

confidence: 97%

“…IT HAS BEEN KNOWN THAT FOLATE (vitamin B 9 ) is absorbed by a specific carrier-mediated transport system from the small intestine (32,33). The mechanism and regulation of the folate transport system had been of great interest because mammals require the ingestion of preformed folate to meet their needs for one-carbon moieties to sustain key biosynthetic reactions.…”

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confidence: 99%

Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model

Inoue¹,

Nakai²,

Ueda³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Proton-coupled folate transporter/heme carrier protein 1 (PCFT/HCP1) has recently been identified as a transporter that mediates the translocation of folates across the cellular membrane by a proton-coupled mechanism and suggested to be the possible molecular entity of the carrier-mediated intestinal folate transport system. To further clarify its role in intestinal folate transport, we examined the functional characteristics of rat PCFT/HCP1 (rPCFT/HCP1) expressed in Xenopus laevis oocytes and compared with those of the carrier-mediated folate transport system in the rat small intestine evaluated by using the everted tissue sacs. rPCFT/HCP1 was demonstrated to transport folate and methotrexate more efficiently at lower acidic pH and, as evaluated at pH 5.5, with smaller Michaelis constant ( Km) for the former (2.4 μM) than for the latter (5.7 μM), indicating its characteristic as a proton-coupled folate transporter that favors folate than methotrexate as substrate. rPCFT/HCP1-mediated folate transport was found to be inhibited by several but limited anionic compounds, such as sulfobromophthalein and sulfasalazine. All these characteristics of rPCFT/HCP1 were in agreement with those of carrier-mediated intestinal folate transport system, of which the Km values were 1.2 and 5.8 μM for folate and methotrexate, respectively, in the rat small intestine. Furthermore, the distribution profile of the folate transport system activity along the intestinal tract was in agreement with that of rPCFT/HCP1 mRNA. This study is the first to clone rPCFT/HCP1, and we successfully provided several lines of evidence that indicate its role as the molecular entity of the intestinal folate transport system.

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Sulfasalazine as Folic Acid Inhibitor in Psoriasis

Halasz¹

1990

Arch Dermatol

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ameter appeared for 2 days. After six injections, the tumor flattened and the surface texture became normal. One week after the end of the treatment a psoriatic plaque 30 mm in diameter developed at the injection site (Fig 2). Psoriatic lesions and basal cell carcinomas remote from the injection site remained unaffected. After a comparable time of treatment the injection of recombinant interferon beta resulted in the development of a psoriatic lesion at the injection site in our patient. Although we have no controls consisting of placebo or insulin injec¬ tions in order to exclude a Koebner phenomenon in our case, it remains unclear whether the induction of psoriatic lesions by injection of interferon is limited to interferon gamma and its specific immunomodulating properties, or is a common side effect of interferons in patients with psori¬ asis.Treatment of basal cell carcinoma with intralesional interferon. J Am Acad Dermatol. 1986;15:437-443. 3. Remy W, Demmler M. \l=O"\rtliche/intratumoraleInterferon-Behandlung von Basaliomen. In: Hofschneider PH, ed. Ergebnisse der Beta-Interferon\x=req-\ Therapie bei chronisch-aktiver Hepatitis B, Multipler Sklerose und Krebserkrankungen. San Francisco, Calif. Zuckschwerdt; 1988:83-86. Sulfasalazine as Folic Acid Inhibitor in PsoriasisTo the Editor.\p=m-\Gupta and colleagues noted improvement of psoriasis in many of their patients treated with sulfasalazine after 8 weeks of therapy.1 They speculate on the mechanism of action of this drug. Changes in eicosanoid levels and immunophenotypic parameters in their series were insufficient to explain the noteworthy improvements. One possible mechanism not discussed by them can be found in the gastroenterology literature, namely interference with folate metabolism. For example, Franklin and Rosenberg2 in 1973 found that orally administered sulfasalazine interfered with folic acid absorption both in patients with inflammatory bowel disease and in normal subjects. Halsted et al3 later extended these findings by confirming that sulfasalazine is a competitive inhibitor of brush border folate conjugase, inhibiting hydrolysis of polyglutamyl folate and decreasing absorption of both polyglutamyl and monoglutamyl folate. They noted that folate malabsorption and deficiency are predictable in most patients using sulfasalazine. Selhub and coworkers,4 using rat liver extracts, demonstrated that sulfasalazine inhibits dihydrofolate reductase, methylenetetrahydrofolate reductase, and serine transhydroxymethylase via competitive inhibition. The drug's breakdown products, sulfapyridine and 5-aminosalicylate,5 did not display similar antifolate properties. Schroder and Campbell6 extrapolated from their data in human subjects that as much as one third of ingested sulfasalazine is absorbed in the small intestine; and Das et al,' using cats, found that 20% to 30% of a dose is absorbed, and then en¬ ters the bile via the enterohepatic circulation. Baum et al,8 using an in vitro system of rat spleen lymphocytes, found that sulfasalazine acts as a ...

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Sulfasalazine Inhibits the Absorption of Folates in Ulcerative Colitis

Cited by 110 publications

References 13 publications

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Functional characterization of PCFT/HCP1 as the molecular entity of the carrier-mediated intestinal folate transport system in the rat model

Sulfasalazine as Folic Acid Inhibitor in Psoriasis

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