Liver dysfunction markedly decreases the inhibition of cytochrome P450 1A2–mediated theophylline metabolism by fluvoxamine

Orlando, Rocco; Padrini, Roberto; Perazzi, Mauro; Martin, Sara De; Piccoli, Pierpaolo; Palatini, Pietro

doi:10.1016/j.clpt.2006.01.012

Cited by 29 publications

(23 citation statements)

References 29 publications

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“…We found only one drug-drug interaction study in cirrhotic patients with a drug selected in our strudy [23], i.e. the interaction of fluvoxamine [IR of CYP1A2 (IR 1A2 ) = 0.99] with theophylline (CR 1A2 = 0.56).…”

Section: Quantitative Prediction Of Drug Interactions In Cirrhosis Pamentioning

confidence: 99%

A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child–Pugh Classification

et al. 2015

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Section: Quantitative Prediction Of Drug Interactions In Cirrhosis Pamentioning

confidence: 99%

A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child–Pugh Classification

et al. 2015

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“…3-MX is a purine derivative and a metabolite of caffeine and theophylline [14,15], and has been monitored biologically in urine and plasma by liquid chromatographic methods [16][17][18][19]. Guanine is a related purine base structure that self-assembles into tetrad structures in biological systems (G-quadruplexes) to form complexes that have been well characterized, theoretically and experimentally [2,[20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Supramolecular Complexes of 3-Methylxanthine with Field Asymmetric Waveform Ion Mobility Spectrometry Combined with Mass Spectrometry

Arthur

Eiceman

Reynolds

et al. 2016

J. Am. Soc. Mass Spectrom.

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Abstract. Miniaturised field asymmetric waveform ion mobility spectrometry (FAIMS), combined with mass spectrometry (MS), has been applied to the study of selfassembling, noncovalent supramolecular complexes of 3-methylxanthine (3-MX) in the gas phase. 3-MX forms stable tetrameric complexes around an alkali metal (Na + , K + ) or ammonium cation, to generate a diverse array of complexes with single and multiple charge states. Complexes of (3-MX) n observed include: singly charged complexes where n = 1-8 and 12 and doubly charged complexes where n = 12-24. The most intense ions are those associated with multiples of tetrameric units, where n = 4, 8, 12, 16, 20, 24. The effect of dispersion field on the ion intensities of the self-assembled complexes indicates some fragmentation of higher order complexes within the FAIMS electrodes (in-FAIMS dissociation), as well as in-source collision induced dissociation within the mass spectrometer. FAIMS-MS enables charge state separation of supramolecular complexes of 3-MX and is shown to be capable of separating species with overlapping mass-to-charge ratios. FAIMS selected transmission also results in an improvement in signal-to-noise ratio for low intensity complexes and enables the visualization of species undetectable without FAIMS.

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“…Within the product label, a DDI study is briefly described in which coadministration of fluvoxamine leads to a 190-fold increase in the AUC of ramelteon (Rozerem; Takeda Pharmaceuticals, Osaka, Japan), which perhaps represents the largest DDI recorded to date for any drug. The mechanism underlying this massive DDI is not described, with the exception that ramelteon is described as being metabolized by CYP1A2, and it is known that fluvoxamine can cause DDI with other drugs known to be cleared by this enzyme, such as theophylline (Rasmussen et al, 1997;Yao et al, 2001;Orlando et al, 2006) and tizanidine (Granfors et al, 2004).…”

mentioning

confidence: 99%

Metabolism of Ramelteon in Human Liver Microsomes and Correlation with the Effect of Fluvoxamine on Ramelteon Pharmacokinetics

Obach

Ryder²

2010

Drug Metab Dispos

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ABSTRACT:Ramelteon is a melatonin receptor agonist used as a treatment for insomnia. It is subject to a remarkably large drug-drug interaction (DDI) caused by fluvoxamine coadministration, resulting in a more than 100-fold increase in exposure. The objective of this study was to determine whether the DDI could be estimated using in vitro metabolism data. Ramelteon was shown to undergo hydroxylation in human liver microsomes to eight metabolites via six pathways. The main routes of metabolism included hydroxylation on the ethyl side chain and the benzylic position of the cyclopentyl ring, as assessed through enzyme kinetic measurements. Hydroxylation at the other benzylic position was observed in human intestinal microsomes. Ramelteon metabolism was catalyzed by CYP1A2, CYP2C19, and CYP3A4 as shown through the use of recombinant human cytochrome P450 enzymes and specific inhibitors. In liver, CYP1A2, CYP2C19, and CYP3A4 were estimated to contribute 49, 42, and 8.6%, respectively, whereas in intestine only CYP3A4 contributes. The in vitro data were used to estimate the magnitudes of DDI caused by ketoconazole, fluconazole, and fluvoxamine. The DDIs caused by the former were reliably estimated (1.82-fold estimated versus 1.82-fold actual for ketoconazole; 2.99-fold estimated versus 2.36-fold actual for fluconazole), whereas for fluvoxamine it was underestimated (11.4-fold estimated versus 128-fold actual). This suggests that there may be a limit on the magnitude of DDI that can be estimated from in vitro data. Nevertheless, the example of the fluvoxamine-ramelteon DDI offers a unique example wherein one drug can simultaneously inhibit multiple enzymatic pathways of a second drug.

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Liver dysfunction markedly decreases the inhibition of cytochrome P450 1A2–mediated theophylline metabolism by fluvoxamine

Cited by 29 publications

References 29 publications

A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child–Pugh Classification

A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child–Pugh Classification

Analysis of Supramolecular Complexes of 3-Methylxanthine with Field Asymmetric Waveform Ion Mobility Spectrometry Combined with Mass Spectrometry

Metabolism of Ramelteon in Human Liver Microsomes and Correlation with the Effect of Fluvoxamine on Ramelteon Pharmacokinetics

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