Identification of quinine metabolites in urine after oral dosing in humans

Bannon, Pierre; Peng, Yu; Cook, James M.; Roy, Louise; Villeneuve, Jean‐Pierre

doi:10.1016/s0378-4347(98)00249-7

Cited by 25 publications

(18 citation statements)

References 21 publications

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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: 62%

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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Section: Time (Hours)mentioning

confidence: 62%

Quinine distribution in mice withplasmodium berghei malaria

Pussard

Bernier

Fouquet

et al. 2003

Eur. J. Drug Metab. Pharmacokinet.

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“…The drug is also used for the treatment of muscle cramps and reversal of multidrug resistance during chemotherapy. In food and beverage industries, it is applied as a bitter flavoring agent in tonic water or tonic-containing mixed beverages [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Polymer-modified glassy carbon electrode for the electrochemical detection of quinine in human urine and pharmaceutical formulations

et al. 2012

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Section: Introductionmentioning

confidence: 99%

“…Although the drug has been used for more than 300 years, its metabolism and elimination in humans is not well elucidated. Even though several metabolites have been identified (Bannon et al, 1998;Mirghani et al, 2001), the relative roles of these metabolites in quinine elimination and their antimalarial activity have not been investigated.The major metabolite of quinine has been reported to be 3-hydroxyquinine just by comparing the peak heights with that of other metabolites in the chromatograms without quantification (Wanwimolruk et al, 1995). Cytochrome P450 3A4 (CYP3A4) is the most abundant isoform in human liver (up to 30%) and involved in the metabolism of more than 50% of clinically used drugs (Kuehl et al, 2001).…”

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confidence: 99%

Enzyme Kinetics for the Formation of 3-Hydroxyquinine and Three New Metabolites of Quinine in Vitro; 3-Hydroxylation by CYP3A4 is Indeed the Major Metabolic Pathway

Mirghani¹,

Yaşar²,

Zheng³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The formation kinetics of 3-hydroxyquinine, 2-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine were investigated in human liver microsomes and in human recombinant-expressed CYP3A4. The inhibition profile was studied by the use of different concentrations of ketoconazole, troleandomycin, and fluvoxamine. In addition, formation rates of the metabolites were correlated to different enzyme probe activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in microsomes from 20 human livers. Formation of 3-hydroxyquinine had the highest intrinsic clearance in human liver microsomes (mean ؎ S.D.) of 11.0 ؎ 4.6 l/min/mg. A markedly lower intrinsic clearance, 1.4 ؎ 0.7, 0.5 ؎ 0.1, and 1.1 ؎ 0.2 l/min/mg was measured for 2-quininone, (10R)-11-dihydroxydihydroquinine and (10S)-11-dihydroxydihydroquinine, respectively. Incubation with human recombinant CYP3A4 resulted in a 20-fold higher intrinsic clearance for 3-hydroxyquinine compared with 2-quininone formation whereas no other metabolites were detected. The formation rate of 3-hydroxyquinine was completely inhibited by ketoconazole (1 M) and troleandomycin (80 M). Strong inhibition was observed on the formation of 2-quininone whereas the formation of (10S)-11-dihydroxydihydroquinine was partly inhibited by these two inhibitors. No inhibition on the formation of (10R)-11-dihydroxydihydroquinine was observed. There was a significant correlation between the formation rates of quinine metabolites and activities of the CYP3A4 selected marker probes. This in vitro study demonstrates that 3-hydroxyquinine is the principal metabolite of quinine and CYP3A4 is the major enzyme involved in this metabolic pathway.Quinine is one of the Cinchona alkaloids used in the treatment of severe forms of malaria (White, 1992). Although the drug has been used for more than 300 years, its metabolism and elimination in humans is not well elucidated. Even though several metabolites have been identified (Bannon et al., 1998;Mirghani et al., 2001), the relative roles of these metabolites in quinine elimination and their antimalarial activity have not been investigated.The major metabolite of quinine has been reported to be 3-hydroxyquinine just by comparing the peak heights with that of other metabolites in the chromatograms without quantification (Wanwimolruk et al., 1995). Cytochrome P450 3A4 (CYP3A4) is the most abundant isoform in human liver (up to 30%) and involved in the metabolism of more than 50% of clinically used drugs (Kuehl et al., 2001). CYP3A4 is reported to catalyze the formation of 3-hydroxyquinine both in vitro (Zhang et al., 1997) and in vivo (Mirghani et al., 1999). In a previous in vivo study, we found that about 30% of a single oral dose was excreted as quinine and 3-hydroxyquinine in human urine (Mirghani et al., 1999). Since quinine is extensively metabolized in the liver, elimination via other metabolic pathways may partly explain this low recovery. Four of the quinine metabolites, 3-hydroxyquinine, 2Ј-quininone, (10S)-11-dihydroxydih...

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Identification of quinine metabolites in urine after oral dosing in humans

Cited by 25 publications

References 21 publications

Quinine distribution in mice withplasmodium berghei malaria

Quinine distribution in mice withplasmodium berghei malaria

Polymer-modified glassy carbon electrode for the electrochemical detection of quinine in human urine and pharmaceutical formulations

Enzyme Kinetics for the Formation of 3-Hydroxyquinine and Three New Metabolites of Quinine in Vitro; 3-Hydroxylation by CYP3A4 is Indeed the Major Metabolic Pathway

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