Pro-inflammatory response and adverse drug reactions: Mechanisms of action of ximelagatran on chemokine and cytokine activation in a monocyte in vitro model

Edling, Ylva; Sivertsson, Louise; Andersson, Tommy; Porsmyr-Palmertz, Margareta; Ingelman‐Sundberg, Magnus

doi:10.1016/j.tiv.2008.06.011

Cited by 12 publications

(9 citation statements)

References 34 publications

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“…Caucasian (N Europe) 5.0 [42] Nevirapine DRB1*01 Caucasian (Europe) 3.0 [48] DRB1*0102 South African -- [49] B*58:01 South African -- [49] Ticlopidine A*3303 Japanese 13.0 [51] B*44:03 Japanese 6.7 [51] Cw*1403 Japanese 7.3 [51] DRB1*1302 Japanese 9.0 [51] DQB1*0604 Japanese 10.1 [51] Tiopronin A*33 B*44 DR6 Japanese -- [52] Ximelagatran DRB1*0701-DQA1*0201 Caucasian (N Europe) 4.4 [37] *Association reduces the risk of drug-induced liver injury. HLA: Human leukocyte antigen.…”

Section: Flucloxacillinmentioning

confidence: 99%

“…Studies performed in isolated hepatocytes and hepatoma cell lines have not detected any direct toxic effects of either ximelagatran or its metabolites [41,42]. The structure of ximelagatran, resembling a short peptide with the peptide bond able to fit in the arginine pocket of thrombin, may be important for the development of an immune-mediated reaction [43].…”

Section: Ximelagatranmentioning

confidence: 99%

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Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Grove

Aithal

2014

Expert Opinion on Drug Metabolism & Toxicology

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Increasing evidence points to a crucial role for the adaptive immune system in the pathogenesis of DILI. Identification of specific HLA alleles as risk factors through large genome-wide association studies has been instrumental in this and in vitro analyses have facilitated improved understanding of the molecular mechanisms. This provides the basis for developing clinical pharmacogenomic applications. Already, genotyping for hypersensitivity HLA risk alleles has been implemented and opportunities for pre-prescription testing in DILI identified. However, although associations are strong, the rarity of DILI means routine testing has not been formally evaluated. Nevertheless, enhanced understanding of how HLA alleles contribute to injury risk is valuable for drug development. Translation of this research into effective pre-emption and primary prevention remains the goal.

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Section: Flucloxacillinmentioning

confidence: 99%

Section: Ximelagatranmentioning

confidence: 99%

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Grove

Aithal

2014

Expert Opinion on Drug Metabolism & Toxicology

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“…On the other hand, the activation of human monocytic cells by other drugs, such as ximelagatran and troglitazone, has been reported recently, although these drugs have been already withdrawn from the market due to idiosyncratic hepatic injury. Ximelagatran increased the release of chemokines from THP-1 cells but the types of released cytokines and the time course of the cytokine release by the drug treatment were different from the case of terbinafine (Edling et al 2008). In addition, troglitazone increased the mRNA expression levels of pro-inflammatory cytokines and chemokines in THP-1 cells, and some of them were affected by co-culture with human hepatoma Huh-7 cells (Edling et al 2009).…”

Section: Discussionmentioning

confidence: 75%

“…In human monocytic THP-1 cells, the mRNA expression levels and/or the release of pro-inflammatory cytokines and chemokines were increased by the treatment with troglitazone or ximelagatran (Edling et al 2008;Edling et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway

et al. 2010

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“…been suggested. 8,9 Ximelagatran was designed as a double prodrug, with moieties masking both the hydrophilic carboxylic acid and amidine groups of the active metabolite melagatran. These molecular modifications increased the log D value and the Caco-2 permeability of the compound and improved the oral bioavailability of melagatran (from 3%-7% to 18%-24%).…”

mentioning

confidence: 99%

Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers

Matsson¹,

Eriksson²,

Knutson³

et al. 2011

The Journal of Clinical Pharmacology

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The biliary excretion of the oral thrombin inhibitor ximelagatran and its metabolites was investigated by using duodenal aspiration in healthy volunteers following intraintestinal dosing. In the first investigation, radiolabeled [(14)C]ximelagatran was administered, enabling quantification of the biliary excretion and identification of metabolites in the bile. In the second study, the effect of erythromycin on the biliary clearance of ximelagatran and its metabolites was investigated to clarify the reported ximelagatran-erythromycin interaction. Approximately 4% of the intraintestinal dose was excreted into bile with ximelagatran and its active form, melagatran, being the most abundant compounds. Four novel ximelagatran metabolites were identified in bile (<0.1% of dose). Erythromycin changed the pharmacokinetics of ximelagatran and its metabolites, with an elevated ximelagatran (78% increase), OH-melagatran (89% increase), and melagatran (86% increase) plasma exposure and higher peak plasma concentrations of the compounds being measured. In parallel, the biliary clearance was moderately reduced. The results suggest that inhibition of hepatobiliary transport is a likely mechanism for the interaction between erythromycin and ximelagatran. Furthermore, the study demonstrated the value of direct bile sampling in humans for the identification of primary biliary metabolites.

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Pro-inflammatory response and adverse drug reactions: Mechanisms of action of ximelagatran on chemokine and cytokine activation in a monocyte in vitro model

Cited by 12 publications

References 34 publications

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Human leukocyte antigen genetic risk factors of drug-induced liver toxicology

Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway

Biliary Excretion of Ximelagatran and Its Metabolites and the Influence of Erythromycin Following Intraintestinal Administration to Healthy Volunteers

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