Human metabolism of [14C]indisulam following i.v. infusion in cancer patients

Beumer, Jan H.; Hillebrand, M. J. X.; Pluim, Dick; Rosing, Hilde; Foley, Karen; Yule, S. M.; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1007/s10637-005-1440-4

Cited by 6 publications

(6 citation statements)

References 17 publications

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“…In the current pharmacogenetic study, the *3 mutation in the CYP2C9 gene reduced the MichaelisMenten elimination rate of indisulam. Thus, the saturable elimination pathway may correspond to hydroxylation of indisulam by CYP2C9 (19).…”

Section: Discussionmentioning

confidence: 99%

“…These CYP2C19 mutations were related to poor metabolism of the CYP2C19 substrate (S)-mephenytoin (23,24) and to a reduction of the clearance of indisulam. Consequently, the linear elimination pathway of indisulam may represent hydroxylation by CYP2C19 (19).…”

Section: Discussionmentioning

confidence: 99%

“…No data regarding the activity or toxicity of the metabolites are available. The major metabolite, Oglucuronide indisulam, is formed by glucuronidation of a hydroxyl metabolite of indisulam (18,19). The hydroxyl metabolite is highly reactive and is immediately conjugated to form O-glucuronide or O-sulfate indisulam.…”

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confidence: 99%

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CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

Zandvliet

Huitema

Copalu

et al. 2007

Clinical Cancer Research

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Purpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation. Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL,V max , K m ) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study. Results:The Michaelis-Menten elimination rate (V max ) was decreased by 27% (P < 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m 2 per mutated allele may be required to normalize this risk. Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.Indisulam is a sulfonamide anticancer agent that disrupts cell cycle progression in the G 1 -S transition (1 -3). Indisulam was well tolerated, but had only moderate single-agent activity in several phase II studies (3 -8). The compound is currently being evaluated as an adjuvant to standard chemotherapy in multiple phase II clinical studies for the treatment of solid tumors.Phase I studies showed that reversible neutropenia and thrombocytopenia were the dose-limiting toxicities of indisulam (9 -14). The pharmacokinetic properties of the compound have been extensively studied (9 -16). Drug clearance decreased with increasing dose, which was indicative for the saturable elimination of indisulam. A semiphysiologic population pharmacokinetic-pharmacodynamic model was developed, which included two parallel pathways for drug elimination: a saturable pathway with Michaelis-Menten kinetics and a linear pathway (16,17). The interindividual variability of the maximal rate of Michaelis-Menten elimination (V max ) was 45%. Differences between patients in hepatic metabolic capacity account for this variability. The pharmacokinetic-pharmacodynamic model showed a clear relationship between pharmacokinetics and hematologic toxicity (17). Patients with impaired metabolic capacity ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

Zandvliet

Huitema

Copalu

et al. 2007

Clinical Cancer Research

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“…The carbonic anhydrase isoenzyme IX is highly overexpressed in hypoxic tumors and presents limited expression in normal tissues, so it is indicated as a molecular target, which can be inhibited by some sulfonamides [3]. Pazopanib [4] and indisulam [5], [6] are examples of sulfonamides in the clinical development of cancer treatment. Recently, a few series of biologically active sulphonamides were synthesized at the Department of Organic Chemistry at the Medical University of Gdańsk [7]–[11].…”

Section: Introductionmentioning

confidence: 99%

Mass Spectrometry Based Identification of Geometric Isomers during Metabolic Stability Study of a New Cytotoxic Sulfonamide Derivatives Supported by Quantitative Structure-Retention Relationships

et al. 2014

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A set of 15 new sulphonamide derivatives, presenting antitumor activity have been subjected to a metabolic stability study. The results showed that besides products of biotransformation, some additional peaks occurred in chromatograms. Tandem mass spectrometry revealed the same mass and fragmentation pathway, suggesting that geometric isomerization occurred. Thus, to support this hypothesis, quantitative structure-retention relationships were applied. Human liver microsomes were used as an in vitro model of metabolism. The biotransformation reactions were tracked by liquid chromatography assay and additionally, fragmentation mass spectra were recorded. In silico molecular modeling at a semi-empirical level was conducted as a starting point for molecular descriptor calculations. A quantitative structure-retention relationship model was built applying multiple linear regression based on selected three-dimensional descriptors. The studied compounds revealed high metabolic stability, with a tendency to form hydroxylated biotransformation products. However, significant chemical instability in conditions simulating human body fluids was noticed. According to literature and MS data geometrical isomerization was suggested. The developed in sillico model was able to describe the relationship between the geometry of isomer pairs and their chromatographic retention properties, thus it supported the hypothesis that the observed pairs of peaks are most likely geometric isomers. However, extensive structural investigations are needed to fully identify isomers’ geometry. An effort to describe MS fragmentation pathways of novel chemical structures is often not enough to propose structures of potent metabolites and products of other chemical reactions that can be observed in compound solutions at early drug discovery studies. The results indicate that the relatively non-expensive and not time- and labor-consuming in sillico approach could be a good supportive tool assisting the identification of cis-trans isomers based on retention data. This methodology can be helpful during the structural identification of biotransformation and degradation products of new chemical entities - potential new drugs.

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“…3,9 The bis-sulfonamide indisulam (IND) is in phase II clinical trials for the treatment of solid tumors and is a potent inhibitor of hCA IX in vitro (K i 24 nM). 14 Despite the widespread use of sulfonamides in the clinic, their systemic administration often causes side effects due to the indiscriminate inhibition of CA isozymes in other tissues. This is prompting the development of tissue specific delivery systems and isozyme specific inhibitors with the aim of producing therapeutics with improved tolerability and efficacy.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides

et al. 2008

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A library of glycoconjugate benzene sulfonamides have been synthesized and investigated for their ability to inhibit the enzymatic activity of physiologically relevant human carbonic anhydrase (hCA) isozymes: hCA I, II, and tumor-associated IX. Our synthetic strategy directly links the known CA pharmacophore (ArSO 2NH 2) to a sugar "tail" moiety through a rigid 1,2,3-triazole linker unit using the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction or "click chemistry". Many of the glycoconjugates were potent CA inhibitors and exhibited some isozyme selectivity. In particular, the methyl-D-glucuronate triazoles 6 and 14 were potent inhibitors of hCA IX (K(i)s 9.9 and 8.4 nM, respectively) with selectivity also favoring this isozyme. Other exceptional compounds included the deprotected beta-D-ribofuranosyl triazole 15 and alpha-D-mannosyl triazole 17, which were potent and selective hCA II inhibitors (K(i) 7.5 nM and K(i) 2.3 nM, respectively). Collectively, the results confirm that modification of ring size, stereochemical configuration, and chain length in the sugar tail moiety of glycoconjugate CA inhibitors permits tunable potency and selectivity that may constitute an important avenue for the future development of efficacious and selective CA-based therapeutics.

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Human metabolism of [14C]indisulam following i.v. infusion in cancer patients

Cited by 6 publications

References 17 publications

CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

Mass Spectrometry Based Identification of Geometric Isomers during Metabolic Stability Study of a New Cytotoxic Sulfonamide Derivatives Supported by Quantitative Structure-Retention Relationships

Inhibition of Carbonic Anhydrases with Glycosyltriazole Benzene Sulfonamides

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