Comparative Bioavailability of Sulindac in Capsule and Tablet Formulations

Reid, Joel M.; Mandrekar, Sumithra J.; Carlson, Elsa C.; Harmsen, William S.; Green, Erin M.; McGovern, Renee M.; Szabó, Éva; Ames, Matthew M.; Boring, Daniel; Limburg, Paul J.

doi:10.1158/1055-9965.epi-07-2510

Cited by 13 publications

(20 citation statements)

References 21 publications

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“…Samples were analyzed by HPLC (Reid et al, 2008). The HPLC system (Shimadzu, Kyoto, Japan) consisted of a pump (CBM-20A) with a UV detector (SPD-20A) and an autosampler (SIL-20A).…”

Section: Methodsmentioning

confidence: 99%

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

Park¹,

Lee²,

Lee³

et al. 2014

Drug Metabolism and Disposition

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This study aimed to investigate the effects of polymorphisms of the flavin-containing mono-oxygenase 3 (FMO3) and flavin-containing mono-oxygenase 6 (FMO6) genes on the pharmacokinetics of sulindac sulfide, the active metabolite of sulindac, in patients with preterm labor. Ten single-nucleotide polymorphisms (SNPs) were genotyped, and plasma sulindac sulfide concentrations were measured at 0, 1.5, 4, and 10 hours after drug administration. The area under the curve from time 0 to the last sampling time point (AUC last ) for sulindac sulfide was obtained. The AUC last of sulindac sulfide was significantly higher in patients with variant-type homozygotes of FMO3 (rs909530) than those with ancestral alleles or heterozygotes. FMO3 (rs2266780) was in complete linkage disequilibrium with FMO6 (rs7885012), and there was marginal significance between the genotypes (P = 0.049). From multiple linear regression models, FMO3 (rs909530) was found to have significant influence on the AUC last of sulindac sulfide after adjusting for gestational age, weight, and all studied SNPs. The predictive contribution of rs909530 to the variability of sulindac sulfide AUC last was 27.0%. In conclusion, the results of this study could help clinicians predict the efficacies and side effects of sulindac in the development of individualized treatment of patients with preterm labor. IntroductionSulindac is a prostaglandin synthetase inhibitor (Nuki, 1983). As prostaglandin increase is observed in both term and preterm labor, prostaglandin inhibitors have been used as tocolytic agents (Karim, 1968). Sulindac contains a chiral sulfoxide moiety and is administered clinically as a racemate. It is an inactive prodrug and is reduced to a pharmacologically active metabolite, sulindac sulfide. Sulindac is also oxidized to an inactive metabolite, sulindac sulfone. The sulfide form is inactivated by flavin-containing mono-oxygenase 3 (FMO3), and the (S)-and (R)-sulindac sulfoxides are also oxidized to sulindac sulfone by FMO3 (Hamman et al., 2000;Hisamuddin and Yang, 2007).Several studies showed that FMO3 gene polymorphisms could result in interindividual and interethnic differences in FMO3 activity (Cashman and Zhang, 2002;Hernandez et al., 2003). The polymorphisms could result in differences in the pharmacokinetics and responses of drugs that are metabolized by FMO3, including sulindac. It was reported that genetic polymorphisms of FMO3 could affect clinical outcomes in patients with sulindac therapy due to adenomatous polypsis. The studied end points were pharmacodynamic responses such as polyposis prevention and regression (Hisamuddin et al., 2004(Hisamuddin et al., , 2005. However, there has been no study conducted on the effects of FMO3 genotypes on the blood concentrations of an active sulindac metabolite in clinical settings.It has been reported that flavin-containing mono-oxygenase 6 (FMO6) has significant sequence homology with FMO3 Hernandez et al., 2004;Hisamuddin and Yang, 2007). However, unlike FMO3, the study of the effects of FMO6...

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“…Samples were analyzed by HPLC (Reid et al, 2008). The HPLC system (Shimadzu, Kyoto, Japan) consisted of a pump (CBM-20A) with a UV detector (SPD-20A) and an autosampler (SIL-20A).…”

Section: Methodsmentioning

confidence: 99%

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

Park¹,

Lee²,

Lee³

et al. 2014

Drug Metabolism and Disposition

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“…Moreover, the higher bioavailability of sulindac sulfi de after metabolic reduction of sulindac, makes this metabolite an ideal inhibitor of LF, since sulindac sulfi de will be more readily available in circulation than sulindac sulfone. [ 28 ] LF protease activity inhibition studies also revealed that both sulindac sulfi de and sulindac sulfone were good inhibitors of LF protease activity. For sulindac sulfi de, an IC 50 of 19.1 μ M was observed (Supplemental Figure 4c), suggesting that this metabolite could be better inhibitor of the anthrax toxin that its parent drug sulindac (IC 50 = 173 μ M).…”

Section: Sulindac Metabolic Derivatives As Inhibitors Of Lf Toxinmentioning

confidence: 92%

“…After a typical dosage of 150 mg, the maximum concentration of sulindac in human blood plasma is of 5.71 ± 2.17 μ g/mL, with a mean half life of 7.8 h. [ 28 ] Sulindac is actually a prodrug that upon oral administration is transformed by the liver to the reduced sulfi de and the oxidized sulfone. Sulindac sulfi de is the actual COX(I/II) inhibitor, while the sulindac sulfone has not been found to have an anti-infl ammatory activity.…”

Section: Sulindac Metabolic Derivatives As Inhibitors Of Lf Toxinmentioning

confidence: 99%

Identification of Toxin Inhibitors Using a Magnetic Nanosensor‐Based Assay

Santiesteban

Kaittanis

Perez

2013

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A magnetic nanosensor-based method is described to screen a library of drugs for potential binding to toxins. Screening is performed by measuring changes in the magnetic relaxation signal of the nanosensors (bMR nanosensors) in aqueous suspension upon addition of the toxin. The Anthrax lethal factor (ALF) is selected as a model toxin to test the ability of our bMR nanosensor-based screening method to identify potential inhibitors of the toxin. Out of 30 molecules screened, sulindac, naproxen and fusaric acid are found to bind LF, with dissociation constants in the low micromolar range. Further biological analysis of the free molecules in solution indicate that sulindac and its metabolic products inhibited LF cytotoxicity to macrophages with IC50 values in the micromolar range. Meanwhile, fusaric acid is found to be less effective at inhibiting LF cytotoxicity, while naproxen does not inhibit LF toxicity. Most importantly, when the sulindac and fusaric acid-bMR nanosensors themselves are tested as LF inhibitors, as opposed to the corresponding free molecules, they are stronger inhibitors of LF with IC50 values in the nanomolar range. Taken together, these studies show that a bMR nanosensors-based assay can be used to screen known drugs and other small molecules for inhibitor of toxins. The method can be easily modified to screen for inhibitors of other molecular interactions and not only the selected free molecule can be study as potential inhibitors but also the bMR nanosensors themselves achieving greater inhibitory potential.

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“…Ongoing concerns regarding the cardiovascular toxicity of selective COX-2 inhibitors [24, 25] have prompted renewed interest in non-selective COX inhibitors, such as sulindac, for chemopreventive applications. [26] In this context, we conducted a randomized, double-blind, phase II trial of sulindac versus placebo among current or former smokers with histologically-confirmed bronchial dysplasia at baseline.…”

Section: Introductionmentioning

confidence: 99%

Randomized phase II trial of sulindac for lung cancer chemoprevention

et al. 2013

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Introduction Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). Methods At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Results Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92). Conclusions Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.

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Comparative Bioavailability of Sulindac in Capsule and Tablet Formulations

Cited by 13 publications

References 21 publications

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

Effects of Single-Nucleotide Polymorphisms of FMO3 and FMO6 Genes on Pharmacokinetic Characteristics of Sulindac Sulfide in Premature Labor

Identification of Toxin Inhibitors Using a Magnetic Nanosensor‐Based Assay

Randomized phase II trial of sulindac for lung cancer chemoprevention

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