In Vitro Metabolism of Leflunomide by Mouse and Human Liver Microsomes

Chan, Eric Chun Yong; New, Lee-Sun

doi:10.2174/187231207783221402

Cited by 7 publications

(6 citation statements)

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“…The UPLC and QTRAPMS systems were controlled by Analyst 1.4.2 software (Applied Biosystems). All the metabolic profiling experiments related to LEF and its metabolites have been previously discussed 15. Product ion scanning (PIS) experiments were performed to profile both LEF and its metabolites, APAP and NAPQI‐GSH in the microsomal incubation samples.…”

Section: Methodsmentioning

confidence: 99%

“…Orally administered LEF is almost completely converted into its pharmacological active metabolite, A77‐1726, and the circulating concentrations of LEF are mostly below the limit of detection 14. Both LEF and A77‐1726 were found to be metabolized in vitro using CD‐1 mouse and human liver microsomes to two hydroxylated metabolites, M1 and M2 15. Each pair of these compounds (LEF/A77‐1726 and M1/M2) is isobaric and structurally similar (Fig.…”

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confidence: 99%

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Pharmaceutical metabolite profiling using quadrupole/ion mobility spectrometry/time‐of‐flight mass spectrometry

Chan

New

Yap

et al. 2009

Rapid Comm Mass Spectrometry

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The use of hybrid quadrupole ion mobility spectrometry time-of-flight mass spectrometry (Q/IMS/TOFMS) in the metabolite profiling of leflunomide (LEF) and acetaminophen (APAP) is presented. The IMS drift times (T(d)) of the drugs and their metabolites were determined in the IMS/TOFMS experiments and correlated with their exact monoisotopic masses and other in silico generated structural properties, such as connolly molecular area (CMA), connolly solvent-excluded volume (CSEV), principal moments of inertia along the X, Y and Z Cartesian coordinates (MI-X, MI-Y and MI-Z), inverse mobility and collision cross-section (CCS). The correlation of T(d) with these parameters is presented and discussed. IMS/TOF tandem mass spectrometry experiments (MS(2) and MS(3)) were successfully performed on the N-acetyl-p-benzoquinoneimine glutathione (NAPQI-GSH) adduct derived from the in vitro microsomal metabolism of APAP. As comparison, similar experiments were also performed using hybrid triple quadrupole linear ion trap mass spectrometry (QTRAPMS) and quadrupole time-of-flight mass spectrometry (QTOFMS). The abilities to resolve the product ions of the metabolite within the drift tube and fragment the ion mobility resolved product ions in the transfer travelling wave-enabled stacked ring ion guide (TWIG) demonstrated the potential applicability of the Q/IMS/TOFMS technique in pharmaceutical metabolite profiling.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmaceutical metabolite profiling using quadrupole/ion mobility spectrometry/time‐of‐flight mass spectrometry

Chan

New

Yap

et al. 2009

Rapid Comm Mass Spectrometry

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“…The latter is supported by studies of leflunomide in cultured hepatocytes, which indicated that Cytochrome P450 mediated metabolism is a prerequisite for leflunomide induced liver injury, whereas teriflunomide is directly, albeit less significantly toxic [12]. Metabolites of teriflunomide have not been observed in human plasma, but studies with human liver microsomes have shown that teriflunomide can be converted via hydroxylation to a metabolite (M1), whereas leflunomide can be converted to either teriflunomide or a different metabolite (M2, also by hydroxylation) [13,14]. If the enzymes responsible for formation of M2 are different from the well characterized conversion pathway of leflunomide to teriflunomide, reduced activity of CYP2C19 is likely to result in increased formation of M2, which may be the toxic metabolite contributing to the side effects associated with leflunomide.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

et al. 2012

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IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

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“…Leflunomide is metabolized by polymorphic phase I enzymes, particularly CYP1A2 (cytochrome P450 1A2), CYP2C and CYP3A4 (cytochrome P450 3A4), but studies [66][67][68][69][70][71] addressing the role of altered metabolism genetically determined and the risk of developing hypersensitivity reactions to leflunomide are still insufficient.…”

Section: Recent Advances In Genetic and Metabolic Biomarkers Of Hypermentioning

confidence: 99%

Drug metabolism and hypersensitivity reactions to drugs

Agúndez

Mayorga²,

García‐Martín³

2015

Current Opinion in Allergy &Amp; Clinical Immunology

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In Vitro Metabolism of Leflunomide by Mouse and Human Liver Microsomes

Cited by 7 publications

References 0 publications

Pharmaceutical metabolite profiling using quadrupole/ion mobility spectrometry/time‐of‐flight mass spectrometry

Pharmaceutical metabolite profiling using quadrupole/ion mobility spectrometry/time‐of‐flight mass spectrometry

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

Drug metabolism and hypersensitivity reactions to drugs

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