Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Zhao, Xuejun; Ishizaki, Takashi

doi:10.1046/j.1365-2125.1997.t01-1-00619.x

Cited by 18 publications

(10 citation statements)

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“…Also the formation of 2Ј-quininone is primarily dependent on CYP3A4 as shown by the extensive inhibition by ketoconazole and troleandomycin. This is consistent with previously reported data for 3-hydroxyquinine, both in vitro (Zhao and Ishizaki, 1997) and in vivo (Mirghani et al, 1999). Partial inhibition was observed by ketoconazole and troleandomycin (58 and 57%, respectively) on the formation of (10S)-11-dihydroxydihydroquinine indicating the involvement of CYP3A4.…”

Section: Discussionsupporting

confidence: 82%

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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Section: Discussionsupporting

confidence: 82%

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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“…C max and AUC for HFM were significantly increased in the presence of tetracycline (Table 1). There was no significant change (P > 0.05) in t max (median (range) 10 (8-12) alone vs 12 (8)(9)(10)(11)(12) h with tetracycline (95% CI -3.3, 2.3)). …”

Section: Drug Volunteermentioning

confidence: 97%

“…Based on a report [11] which suggests that tetracycline is a substrate or inhibitor for CYP3A4, the enzyme that metabolizes halofantrine [12], a metabolic interaction between the two compounds might be expected. However, the increased plasma concentrations of the metabolite HFM in the presence of tetracycline and the finding that doxycycline, a tetracycline analogue, does not inhibit the metabolism of halofantrine in human liver microsomes [19] suggests that the interaction between tetracycline and halofantrine does not have a metabolic basis.…”

Section: Discussionmentioning

confidence: 99%

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Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers

Bassi¹,

Onyeji²,

Ukponmwan³

2004

Brit J Clinical Pharma

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AimsTo investigate the effect of tetracycline co-administration on the pharmacokinetics of halofantrine in healthy subjects. MethodsEight healthy males were each given 500 mg single oral doses of halofantrine alone, or with tetracycline (500 mg 12 hourly for 7 days), in a crossover fashion. Blood samples collected at predetermined intervals were analyzed for halofantrine and its major metabolite, desbutylhalofantrine (HFM), using a validated HPLC method. ResultsCo-administration of tetracycline and halofantrine resulted in a significant increase ( P < 0.05) in the maximum plasma concentration ( C max ), total area under the concentration-time curve (AUC), and terminal elimination half-life ( t 1/2,z ), compared with halofantrine alone. ( C max 0.43 ± 0.14 vs 1.06 ± 0.44 m g ml -1 (95% CI on the difference 0.30, 0.95); AUC 32.0 ± 13.6 vs 63.7 ± 20.1 m g ml -1 h (95% CI 14.2, 49.1); t 1/2,z: 90.8 ± 17.9 vs 157.4 ± 57.4 h (95% CI 21.7, 111.5)). Similarly, tetracycline caused a significant increase ( P < 0.05) in the AUC and C max of HFM. ConclusionsTetracycline co-administration significantly increases the plasma concentrations of halofantrine and its major metabolite.

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“…Ketoconazole is well known to potently inhibit CYP3A4 activity in human liver microsomes [25]. Since the major metabolic pathway of both QN and HF is through CYP3A4 subfamily [26,27], inhibition of the isoenzyme by KTZ could account for the increased plasma QN and HF levels. In the present study, and in the light of the above-mentioned data, we examined the inhibitory effects of KTZ on the antischistosomal potential of QN and HF against adult S. mansoni infection in mice, by evaluating parasitological, histopathological, and biochemical parameters.…”

Section: Introductionmentioning

confidence: 99%

Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

et al. 2013

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The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.

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Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes

Cited by 18 publications

References 9 publications

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

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

Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers

Effect of Ketoconazole, a Cytochrome P450 Inhibitor, on the Efficacy of Quinine and Halofantrine against Schistosoma mansoni in Mice

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