Enterohepatic circulation of sulindac and metabolites

Dujovne, Carlos A.; Pitterman, Arthur; Vincek, William C.; Dobrinska, Michael R.; Davies, Richard O.; Duggan, D E

doi:10.1038/clpt.1983.26

Cited by 23 publications

(8 citation statements)

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“…As noted (Table 3) the excretion of sulindac in bile (51, 52) and the presence of its metabolites in gallstones (53) indicate a likely biological connection since gallstones predispose to gallbladder cancer (54). If this association is confirmed, questions needing to be answered are whether sulindac increases risk of gallstones, whether presence of sulindac metabolites in gallstones increases their carcinogenicity, or whether sulindac in bile increases risk of both stones and cancer without stones as a necessary intermediate step to cancer.…”

Section: Discussionmentioning

confidence: 87%

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened

Friedman

Udaltsova

Chan

et al. 2009

Cancer Causes Control

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Objective-We screened commonly used prescription drugs for possible carcinogenic effects.Methods-In a large health care program we identified 105 commonly used drugs, not previously screened. Recipients were followed for up to 12½ years for incident cancer. Nested case-control analyses of 55 cancer sites and all combined included up to ten matched controls per case, with lag of at least two years between drug dispensing and cancer. Positive associations entailed a relative risk (RR) of 1.50, with p≤ 0.01 and higher risk for three or more, than for one prescription. Evaluation included further analyses, searches of the literature, and clinical judgment.Results-There were 101 associations of interest for 61 drugs. Sixty-six associations were judged to have involved substantial confounding. We found evidence that of the remaining 35, the following associations may not be due to chance: sulindac with gallbladder cancer and leukemia, hyoscyamine with non-Hodgkin lymphoma, nortriptyline with esophageal and hepatic cancer, oxazepam with lung cancer, both fluoxetine and paroxetine with testicular cancer, hydrochlorothiazide with renal and lip cancer, and nifedipine with lip cancer.Conclusions-These preliminary findings suggest that further studies are indicated regarding sulindac, hyoscyamine, nortriptyline, oxazepam, fluoxetine, paroxetine, hydrochlorothiazide and nifedipine.Many adults and children take medications regularly, yet relatively few drugs have undergone significant long-term post-marketing surveillance for adverse effects, including elevated cancer risk. In September 2006 the Institute of Medicine's Committee on the Assessment of the US Drug Safety System recommended substantial increases in safety studies of marketed drugs (1). [6][7][8][9][10][11][12]. The results of our previous screening studies were cited as providing data on 18 of the drugs evaluated and as the only source of data on humans for 9 of these.With region-wide implementation achieved by August, 1994, the Kaiser Permanente Medical Care Program (KPMCP) in northern California employs a Pharmacy Information Management System (PIMS) that records all prescriptions dispensed to its subscribers, now numbering over 3 million. Drawing upon this newer resource and a region-wide cancer registry we have screened for possible carcinogenic effects 105 commonly used drugs that were not studied in the previous smaller database, mostly because they were introduced after 1973. We here present associations that are sufficiently strong and convincing, by both a few screening criteria and further evaluation, that more detailed study is suggested to help differentiate those that are causal from those that are due to unrecognized confounding or simply to chance, given the large number of possible associations generated. Study population and methods SettingThe KPMCP is an integrated prepaid health care delivery system that provides comprehensive inpatient and outpatient care, including pharmacy services, to over 3 million current members, who comprise ab...

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Section: Discussionmentioning

confidence: 87%

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened

Friedman

Udaltsova

Chan

et al. 2009

Cancer Causes Control

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“…There was no relationship between the plasma concentration of exisulind and the administered dose or any other pretreatment condition including renal or hepatic function, weight, height, age, or gender. Interestingly, the majority of exisulind undergoes biliary excretion with no evidence of metabolism by the cytochrome P450 isoenzyme system, which can be a major source of interpatient variability (19,26). Thus, the etiology of this variability may be related to hepatobiliary transporters that have also been implicated in the gastrointestinal toxic effects of a range of agents including NSAIDS, irinotecan, and methotrexate (27,28).…”

Section: Discussionmentioning

confidence: 99%

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

Witta¹,

Gustafson²,

Pierson³

et al. 2004

Clinical Cancer Research

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Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study.Experimental Design: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150 -250 mg) given orally twice daily and docetaxel (30 -36 mg/m 2 ) administered intravenously on days 1, 8, and 15 of a 4-week cycle.Results: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m 2 . Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed.Conclusions: The combination of docetaxel (36 mg/m 2 , weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.

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“…An important phenomenon in the metabolism of sulindac is the enterohepatic circulation of the three redox forms with rate of biliary secretion of sulindac, sulfoxide > sulfone > sulfide [62]. Since the gastrointestinal toxicity of NSAIDs is partly determined by the exposure of the gut mucosa to the active form, this disproportionate secretion of prodrug relative to active drug provides a theoretical basis for the relatively low toxicity of sulindac [64].…”

Section: Gastrointestinal Implications Of Fmo3 Polymorphismsmentioning

confidence: 99%

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

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Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

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Enterohepatic circulation of sulindac and metabolites

Cited by 23 publications

References 0 publications

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

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