Identification of new urinary metabolites in man of quinine using methane chemical ionization gas chromatography-mass spectrometry

Liddle, C.; Graham, Garry G.; Christopher, R. K.; Bhuwapathanapun, Supapong; Duffield, A. M.

doi:10.3109/00498258109045277

Cited by 16 publications

(5 citation statements)

References 5 publications

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“…The cinchona alkaloid anti-malarial agent, quinine is extensively metabolized in vivo , and many of the resulting metabolites have been reported both in urine and plasma [4,7,8,16]. While these studies have largely used synthetic metabolites of the diasteriomer quinidine as reference standards for HPLC identification rather than direct observation via accurate mass MS, the consensus assignments are not in question.…”

Section: Discussionmentioning

confidence: 99%

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CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

Marcsisin

Jin

Bettger

et al. 2013

Malar J

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BackgroundThe naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug.MethodsIncubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MSE analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.ResultsThe metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes.ConclusionsTaken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.

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Section: Discussionmentioning

confidence: 99%

“…They further noted that neither observation correlated with a significant increase in the ratio of 3-hydroxyquinine, a major metabolite, in the urine [4,8]. Other metabolites have been observed in urine such as 2’-oxoquininone and O-desmethylquinine which have not been assigned to specific CYP pathways [6,7,16]. …”

Section: Discussionmentioning

confidence: 99%

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

Marcsisin

Jin

Bettger

et al. 2013

Malar J

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“…3 0 . 3 5 In general, the 'open' conformation is preferred for all free bases with a C-9-hydroxy group, as well as for all protonated or complexed forms.' 9 .…”

Section: Discussionmentioning

confidence: 99%

(3S)-3-hydroxyquinidine, the major biotransformation product of quinidine. Synthesis and conformational studies. X-Ray molecular structure of (3S)-3-hydroxyquinidine methanesuiphonate

Carroll¹,

Abraham²,

Gaetano³

et al. 1991

J. Chem. Soc., Perkin Trans. 1

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Hydroxyquinidine, the major metabolite of the Cinchona alkaloid quinidine, vvas prepared by synthetic chemical modification or microbial oxidation of quinidine. The structure of this metabolite has been demonstrated to be (3S)-3-hydroxyquinidine by 'H and 13C NMR, IR, UV and mass spectral analysis. Previously published comparisons of the 13C N M R spectra of 3-hydroxyquinidine and model compounds were used to establish the absolute stereochemistry of the metabolite (see ref. 8). This assignment has been verified by single-crystal X-ray analysis of ( 3 s ) -3hydroxyquinidine methanesulphonate. The gas-and solution-phase conformational preference of the metabolite derived from molecular modelling and NOE studies are compared with the conformation observed by X-ray crystallography.

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“…The two metabolites observed in theblood and tissues of our mice have retention times similar to those obtained with human samples. As compared to previous chromatographic studies, the M, metabolite is probably the 3-hydroxyderivative of quinine and the more polar M 1 metabolite is suspected to be the 10,l l-dihydroxydihydroquinine (22,23,24). However, the lack of authentic standards did not allow us to identify or quantify these metabolites.…”

Section: Time (Hours)mentioning

confidence: 82%

Quinine distribution in mice withplasmodium berghei malaria

Pussard

Bernier

Fouquet

et al. 2003

Eur. J. Drug Metab. Pharmacokinet.

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The disposition of a single 80 mg/kg injection of quinine base was compared in control and Plasmodium berghei-infected mice. Pharmacokinetic parameters were determined on repeated whole blood samples from caudal vein (experiment 1) and quinine distribution was evaluated in tissues and blood fractions from mice sacrificed two hours post dosing (experiment 2). Quinine concentrations were assessed by high performance liquid chromatography with fluorometric detection. Whole blood concentrations and AUC(0 - infinity) of quinine increased in a parasitaemia-dependent manner. Quinine blood clearance and peak blood concentrations of metabolites negatively correlated with the parasitaemia. The apparent distribution volume of quinine only decreased in severely ill mice. Quinine concentrations rise in a parasitaemia-dependent manner in homogenates of spleen, lungs and kidney and in erythrocyte pellets. The negative relationship, observed between the parasitaemia and the tissue-to-whole blood ratio for muscle, heart, liver and brain, contributes to the reduction of the blood distribution volume. Quinine uptake by muscle and heart was dependent on the free fraction of plasma quinine. The liver and brain concentrations of quinine were similar in control and infected mice. The tissue-to-plasma free fraction ratios decrease when the parasitaemia rises suggesting a restrictive uptake of quinine by these tissues. In conclusion. P. berghei malaria decreases both total clearance and apparent volume of distribution with a heterogeneous redistribution of quinine between the tissues.

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Identification of new urinary metabolites in man of quinine using methane chemical ionization gas chromatography-mass spectrometry

Cited by 16 publications

References 5 publications

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

(3S)-3-hydroxyquinidine, the major biotransformation product of quinidine. Synthesis and conformational studies. X-Ray molecular structure of (3S)-3-hydroxyquinidine methanesuiphonate

Quinine distribution in mice withplasmodium berghei malaria

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