5-Aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine

Hande, Scott A.; Wilson-Rich, Noah; Bousvaros, Athos; Zholudev, Anna; Maurer, Rie; Banks, Peter A.; Makrauer, Frederick L.; Reddy, Sarathchandra I.; Burakoff, Robert; Friedman, Sonia

doi:10.1097/01.mib.0000206544.05661.9f

Cited by 92 publications

(68 citation statements)

References 29 publications

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“…In contrast to the previous in vitro study (K i ϭ 12 M) (Lewis et al, 1997), in our hands olsalazine was a relatively weak inhibitor of TPMT (K i ϭ 208 M), applying our experimental conditions. This finding is in correlation with several clinical studies in which aminosalicylate therapy was not a predictor for either side effects of thiopurine therapy, low TPMT activity, or 6-MMP levels (Dewit et al, 2002;Gisbert et al, 2006;Hande et al, 2006). None of the previous studies which aimed to study olsalazine potential to inhibit TPMT have used RBC as a source of enzyme.…”

Section: Resultssupporting

confidence: 71%

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

Oselin¹,

Anier²

2007

Drug Metab Dispos

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ABSTRACT:Thiopurine S-methyltransferase (TPMT) is a biotransformation phase II enzyme responsible for the metabolic inactivation of thiopurine drugs. The present study was carried out to investigate the inhibitory potential of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) on human TPMT activity in vitro. TPMT activity was measured in pooled human erythrocytes in the absence and presence of various NSAIDs using the previously published high-performance liquid chromatography-UV method. Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67) is a biotransformation phase II enzyme involved in inactivation of the thiopurine drugs azathioprine, 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG) (Anglicheau et al., 2002). Individuals with genetically determined low or intermediate TPMT activity have a higher risk for side effects when treated with standard doses of thiopurines. Similarly, individuals with high TPMT activity taking 6-MP or 6-TG may be at higher risk for side effects when treated simultaneously with drugs that inhibit TPMT. Woodson et al. (1983) studied benzoic acid and a series of its derivatives for their potential to inhibit TPMT. Using the purified human kidney enzyme, they found that acetylsalicylic acid and its active metabolite salicylic acid inhibited TPMT. No in vivo studies to confirm the clinical significance of this interaction have been performed. Aminosalicylates, such as sulfasalazine and olsalazine, used in the treatment of ulcerative colitis and Crohn's disease, contain benzoic acid in their chemical structures. In several clinical trials, increased 6-TG nucleotide levels have been found in patients with inflammatory bowel disease treated with thiopurines and aminosalicylates compared with thiopurine monotherapy (Lowry et al., 2001;Dewit et al., 2002). In vitro studies using a recombinant human enzyme confirmed that olsalazine, 5-aminosalicylic acid, and sulfasalazine are noncompetitive inhibitors of TPMT (Szumlanski and Weinshilboum, 1995;Lewis et al., 1997).In addition to benzoic acid derivatives, clinically significant interactions via TPMT inhibition by furosemide, bendroflumethiazide, and trichlormethiazide may occur when administered simultaneously with thiopurines (Lysaa et al., 1996). Drugs such as prednisone, prednisolone, 6-methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim-sulfamethoxazole, often used simultaneously with thiopurines in leukemic patients, had no effect on TPMT activity in vitro using lysates of red blood cells (RBC) (Jacqz-Aigrain et al., 1994).Nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit pharmacological effects similar to those of aminosalicylates. These agents also have common features in their chemical structure. We hypothesized that structural determinants responsible for the pharmacological action of NSAIDs might be involved in the inhibition of TPMT in a manner similar to aminosalicylates and benzoic acid derivatives. The potential for diclofenac, lornoxicam, piroxicam, meloxicam, ibuprofen, ketoprofen, flurbiprofen, naproxen, cele...

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Section: Resultssupporting

confidence: 71%

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

Oselin¹,

Anier²

2007

Drug Metab Dispos

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“…Another retrospective study done on 126 IBD patients reported the same conclusion. 67 The interaction leads to higher 6-TGN levels, probably due to diminished TPMT activity. Previous studies have established that 5-ASA medications and their metabolites inhibit TPMT activity in vitro.…”

Section: Discussionmentioning

confidence: 99%

Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease

Ding

Zhang

Liu

et al. 2012

Inflammatory Bowel Diseases

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“…In a retrospective study of 126 adults and children with IBD on stable thiopurine doses, patients also taking aminosalicylates were shown to have mean 6-TGN levels 48 pmol/8 Â 10 8 RBC greater than those on thiopurines alone (P ¼ 0.03). 39 Subsequently, in a small prospective study of 26 patients on stable thiopurine doses, metabolites were monitored as first 2 g, then 4 g daily of mesalamine were added for 1 month each before being discontinued. 6-TGN levels rose in a dose-dependent manner from 243 pmol/8 Â 10 8 RBC in patients on thiopurine monotherapy to 326 pmol/8 Â 10 8 RBC in the 2 g mesalamine group, to 396 pmol/8 Â 10 8 RBC in the 4 g mesalamine group, before dropping again to 286 pmol/8 Â 10 8 RBC after aminosalicylates were stopped (P < 0.05).…”

Section: Using Concomitant Drugs To Optimize Thiopurine Therapymentioning

confidence: 99%

Optimizing thiopurine therapy in inflammatory bowel disease

Chevaux

Peyrin–Biroulet

Sparrow

2011

Inflammatory Bowel Diseases

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Despite recent advances, the therapeutic armamentarium for inflammatory bowel disease (IBD) is still limited. In addition, a step-up approach is recommended for most IBD patients. Thus, optimizing each medical therapy before switching to another drug class is the rule in clinical practice. Conventional therapies for IBD have not received the same amount of attention as biologic therapies over the last decade. However, due to their efficacy, safety, and low cost the thiopurine drugs azathioprine and 6-mercaptopurine remain the backbone of therapy for IBD. Pharmacogenomic advances and increased knowledge of their metabolism are allowing dosage optimization. Herein, after describing the pharmacogenetics and pharmacokinetics of thiopurines, we will discuss how to optimize thiopurine therapy. We will then underscore the need to take into account safety issues when optimizing thiopurine treatment.

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5-Aminosalicylate therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-mercaptopurine or azathioprine

Cited by 92 publications

References 29 publications

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease

Optimizing thiopurine therapy in inflammatory bowel disease

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