An LC–MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model

Jin, Xiannu; Pybus, Brandon; Marcsisin, Sean R.; Logan, Timothy M.; Luong, ThuLan; Sousa, Jason; Matlock, N.; Collazo, V.; Asher, Constance O.; Carroll, Dustin; Olmeda, Raul; Walker, Larry; Kozar, Michael P.; Meléndez, Víctor

doi:10.1007/s13318-013-0139-8

Cited by 33 publications

(30 citation statements)

References 15 publications

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“…PQ is extensively metabolized both in vitro in the presence of hepatic microsomes and in vivo (8)(9)(10)(11)(16)(17)(18). The predominant and most thoroughly studied metabolite of PQ is the carboxyl form, carboxyprimaquine (CPQ) (19).…”

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confidence: 99%

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Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

Potter

Xie

Vuong

et al. 2015

Antimicrob Agents Chemother

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Primaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studied in vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity. P rimaquine (PQ) is the only FDA-approved drug for treatment of relapsing infections with malarial strains, including Plasmodium vivax and P. ovale (1-3). PQ belongs to the 8-aminoquinoline (8AQ) class of antimalarial compounds, among which several molecules, including PQ, have potent antihypnozoite activity (2, 4, 5). Low doses of PQ are also recommended for malaria transmission-blocking efforts due to PQ's gametocidal activity (6, 7). PQ's utility in malaria treatment and potential use in malarial transmission reduction and malaria eradication efforts require an understanding of the molecular species involved in its mechanism of action.Recent reports have shown that PQ requires metabolic activation by the cytochrome P450 (CYP) 2D isoenzymes for liver-stage antimalarial activity in both mouse studies (CYP 2D) and human studies (CYP 2D6) (8-11). Pybus et al. demonstrated that PQ was active only in mice capable of metabolizing CYP 2D6 substrates. Deletion of the mouse enzyme closest to human CYP 2D6 (mouse CYP 2D22 via deletion of the CYP 2D gene cluster) in mice completely blocked liver-stage antimalarial activity in vivo (10). The study by Bennett et al. demonstrated a direct link between CYP 2D6 metabolizer status and PQ efficacy for P. vivax treatment in several human subjects (8). PQ therapy is of significant importance for P. vivax radical cure, presumptive antirelapse therapy (PART), and malaria eradication efforts, and the requirement of CYP 2D6 metabolism for PQ efficacy is problematic because CYP 2D6 is highly polymorp...

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confidence: 99%

“…Recent reports have shown that PQ requires metabolic activation by the cytochrome P450 (CYP) 2D isoenzymes for liver-stage antimalarial activity in both mouse studies (CYP 2D) and human studies (CYP 2D6) (8)(9)(10)(11). Pybus et al demonstrated that PQ was active only in mice capable of metabolizing CYP 2D6 substrates.…”

mentioning

confidence: 99%

Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

Potter

Xie

Vuong

et al. 2015

Antimicrob Agents Chemother

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“…The urinary excretion of PQ over 24 h was less than 1% of the dose. The following studies Jin et al, 2014) supported hepatic metabolism as the main elimination route of PQ. G6PD status did not influence the pharmacokinetics of PQ and vice versa.…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 68%

“…The total clearance is approximately 300 to 600 ml/min with renal clearance of less than 1% (3 to 20 ml/min) of the administered dose over 24 h. Hepatic metabolsim of PQ is via monoamine oxidases (A and B), cytochrome P450 (CYP3A4, CYP1A2, and CYP2D6), and flavin-containing monoamineoxygenase 3 enzymes. Several of the identified (for example, CPQ and 6-methoxy-8-aminoquinoline) and unidentified metabolites are detectable in plasma or urine (Constantino et al, 1999;Bennett et al, 2013;Pybus et al, 2013;Jin et al, 2014). The biotransformation pathways important for its therapeutic and toxic effects of PQ remain unclear, but recent evidence suggests that CYP2D6 may play a crucial role in generating the active intermediate metabolites (Constantino et al, 1999;Pybus et al, 2012;Bennett et al, 2013;Jin et al, 2014).…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

“…Several of the identified (for example, CPQ and 6-methoxy-8-aminoquinoline) and unidentified metabolites are detectable in plasma or urine (Constantino et al, 1999;Bennett et al, 2013;Pybus et al, 2013;Jin et al, 2014). The biotransformation pathways important for its therapeutic and toxic effects of PQ remain unclear, but recent evidence suggests that CYP2D6 may play a crucial role in generating the active intermediate metabolites (Constantino et al, 1999;Pybus et al, 2012;Bennett et al, 2013;Jin et al, 2014). The major plasma metabolite CPQ is however unlikely to be directly relevant to antimalarial activity .…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

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A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

Chukanchitipat¹,

Na‐Bangchang²

2017

Afr. J. Pharm. Pharmacol.

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The blood schizontocidal chloroquine (CQ) and the tissue schizontocidal and gametocytocidal primaquine (PQ) remain the mainstay treatment of Plasmodium vivax and Plasmodium ovale infections for more than six decades. The review focuses on the clinical pharmacokinetic studies of both drugs in Thai population that have provided useful information for clinical application in the treatment of malaria. There appears to be no major differences in the pharmacokinetics of both drugs with respect to the influences of ethinicity, acute phase malaria infection, and G6PD status. The increase in systemic exposure of CQ and/or its metabolite mono-desethylchlorooquine (DECQ) following oral administration could be due to change in the absorption kinetics during acute phase infection. The high clinical efficacy of CQ for treatment of P. vivax infection in Thailand supports this benefitial pharmacokinetic change. Transiently high and toxic plasma/whole blood concentrations of CQ following intravenous infusion at high rate is explained by the pharmacokinetic characteristics of CQ. Pharmacokinetics of PQ following repeated dosing in most studies appears to be similar to that following a single dosing. This suggests that auto-inhibition of PQ metabolism during multiple dosing is unlikely. Coadministration of CQ, dihydroartemisinin-piperaquine (DHA-PIP), and pyronaridine-artesunate (PYR-ARS) significantly altered the pharmacokinetics of PQ. In the presence of these drugs, PQ exposure was significantly increased. The apparent volume of distribution of PQ was reduced when coadministered with PYR-ARS. In addition, plasma concentrations of CPQ were significantly increased in the presence of CQ. Clinical relevance of these interactions needs to be confirmed.

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8‐Aminoquinolines with an Aminoxyalkyl Side Chain Exert in vitro Dual‐Stage Antiplasmodial Activity

et al. 2019

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A series of novel 8‐aminoquinolines (8‐AQs) with an aminoxyalkyl side chain were synthesized and evaluated for in vitro antiplasmodial properties against asexual blood stages, liver stages, and sexual stages of Plasmodium falciparum. 8‐AQs bearing 2‐alkoxy and 5‐phenoxy substituents on the quinoline ring system were found to be the most promising compounds under study, exhibiting potent blood schizontocidal and moderate tissue schizontocidal in vitro activity.

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An LC–MS based study of the metabolic profile of primaquine, an 8-aminoquinoline antiparasitic drug, with an in vitro primary human hepatocyte culture model

Cited by 33 publications

References 15 publications

Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

8‐Aminoquinolines with an Aminoxyalkyl Side Chain Exert in vitro Dual‐Stage Antiplasmodial Activity

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