Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Tekwani, Babu L.; Avula, Bharathi; Sahu, Rajnish; Chaurasiya, Narayan D.; Khan, Shabana I.; Jain, S. K.; Fasinu, Pius S.; Herath, H. M. T. Bandara; Stanford, Donald A.; Nanayakkara, N. P. Dhammika; McChesney, James D.; Yates, Travis W.; ElSohly, Mahmoud A.; Khan, Ikhlas A.; Walker, Larry

doi:10.1124/dmd.114.061127

Cited by 21 publications

(36 citation statements)

References 43 publications

(55 reference statements)

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“…Substrate concentrations, as initially titrated, showed optimal metabolism at 20 µM (Km = 37 µM). Although this is higher than expected peak plasma concentrations in humans as we earlier reported (<2 µM) [ 15 ], it approximates expected liver concentrations of PQ, which we observed to be—at therapeutic doses about 20 times higher than plasma in our studies in mice [ 22 ]. The viable cell counts in the drug-free incubation at the predetermined time-points were similar to those of the PQ-containing incubates, suggesting the absence of PQ-induced direct hepatocellular toxicity (Fig.…”

Section: Resultssupporting

confidence: 67%

“…Oxidation of PQ by MAO results in formation of an aldehyde metabolite, which is further oxidized or reduced to the stable metabolites namely, carboxyprimaqine (CPQ) and PQ-alcohol, respectively. CPQ had been identified as the major circulating human metabolite of racemic PQ [ 14 , 15 ]. Pharmacokinetic studies of racemic PQ in mice, monkeys and humans have shown that CPQ rapidly appeared in the plasma and was predominantly the (−)-form [ 9 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…CPQ had been identified as the major circulating human metabolite of racemic PQ [ 14 , 15 ]. Pharmacokinetic studies of racemic PQ in mice, monkeys and humans have shown that CPQ rapidly appeared in the plasma and was predominantly the (−)-form [ 9 , 15 , 16 ]. The current study is aimed at characterizing the kinetics of metabolic profiles of the individual PQ enantiomers in human hepatocytes, where both the CYP and MAO pathways are present.…”

Section: Introductionmentioning

confidence: 99%

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Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

Fasinu

Avula

Tekwani

et al. 2016

Malar J

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BackgroundThe clinical utility of primaquine (PQ), used as a racemic mixture of two enantiomers, is limited due to metabolism-linked hemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. The current study investigated differential metabolism of PQ enantiomers in light of the suggestions that toxicity and efficacy might be largely enantioselective.MethodsStable isotope 13C-labelled primaquine and its two enantiomers (+)-PQ, (−)-PQ were separately incubated with cryopreserved human hepatocytes. Time-tracked substrate depletion and metabolite production were monitored via UHPLC–MS/MS.ResultsThe initial half-life of 217 and 65 min; elimination rate constants (λ) of 0.19 and 0.64 h−1; intrinsic clearance (Clint) of 2.55 and 8.49 (µL/min)/million cells, which when up-scaled yielded Clint of 6.49 and 21.6 (mL/min)/kg body mass was obtained respectively for (+)- and (−)-PQ. The extrapolation of in vitro intrinsic clearance to in vivo human hepatic blood clearance, performed using the well-stirred liver model, showed that the rate of hepatic clearance of (+)-PQ was only 45 % that of (−)-PQ. Two major primary routes of metabolism were observed—oxidative deamination of the terminal amine and hydroxylations on the quinoline moiety of PQ. The major deaminated metabolite, carboxyprimaquine (CPQ) was preferentially generated from the (−)-PQ. Other deaminated metabolites including PQ terminal alcohol (m/z 261), a cyclized side chain derivative from the aldehyde (m/z 241), cyclized carboxylic acid derivative (m/z 257), a quinone-imine product of hydroxylated CPQ (m/z 289), CPQ glucuronide (m/z 451) and the glucuronide of PQ alcohol (m/z 437) were all preferentially generated from the (−)-PQ. The major quinoline oxidation product (m/z 274) was preferentially generated from (+)-PQ. In addition to the products of the two metabolic pathways, two other major metabolites were observed: a prominent glycosylated conjugate of PQ on the terminal amine (m/z 422), peaking by 30 min and preferentially generated by (+)-PQ; and the carbamoyl glucuronide of PQ (m/z 480) exclusively generated from (+)-PQ.ConclusionMetabolism of PQ showed enantioselectivity. These findings may provide important information in establishing clinical differences in PQ enantiomers.

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Section: Resultssupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

Fasinu

Avula

Tekwani

et al. 2016

Malar J

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“…8 a role in the metabolism that occurs both in vitro and in vivo (Fasinu, et al, 2014;Tekwani, et al, 2015).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Marcsisin

Reichard

Pybus

2016

Pharmacology & Therapeutics

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Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threatening hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.

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“…Recent studies of PQ metabolism have revealed interesting new information about the metabolic pathways, suggesting that in humans the two enantiomers of PQ (which is used as a racemic mixture) are differentially metabolized to CPQ [ 20 ]. While the R (–) form of PQ is readily converted to CPQ, the S (+) form is much less so, and in fact >95 % of the CPQ circulating is attributable to R (–) PQ.…”

Section: Introductionmentioning

confidence: 99%

Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine

Fasinu

Tekwani

Avula

et al. 2016

Malar J

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BackgroundThere has been some evidence to suggest that the addition of chloroquine (CQ) or quinine (QN) to 8-aminoquinoline (8-AQ) treatment regimens may increase the therapeutic efficacy of the 8-AQ and simultaneously mitigate against its haemolytic toxicity. However, both CQ and QN are considered effective, although perhaps moderate inhibitors of CYP2D6, an enzyme now regarded as necessary for primaquine (PQ) pharmacologic activity. An understanding of the influence of CQ and QN on the metabolism of PQ may shed light on the potential mechanisms of the beneficial interaction.MethodsDifferential metabolism of PQ enantiomers by recombinant human CYP2D6, monoamine oxidase A (MAO), and cryopreserved human hepatocytes in the presence/absence of CQ and QN.ResultsBoth CQ and QN significantly inhibited the activity of CYP2D6. PQ depletion by MAO and human hepatocytes was not affected significantly by the presence of CQ and QN. CYP2D6-mediated hydroxylation was largely suppressed by both CQ and QN. The formation of the primary deaminated metabolites, including carboxyprimaquine (CPQ) and cyclized side chain derivative from the aldehyde (m/z 241), was not sensitive to the presence of CQ and QN. However, the appearance of the glucuronides of CPQ and PQ alcohol were significantly suppressed. CQ and QN also inhibited the appearance of the m/z 257 metabolite with a similar pattern, suggesting that it may be derived from the CPQ conjugate. The apparent quinone-imine of CPQ (m/z 289) was only partially suppressed by both QN and CQ, but with a differential pattern of inhibition for the two drugs. The m/z 274 (quinone-imine of a ring-hydroxylated PQ metabolite) and m/z 422 (an apparent glucose conjugate of PQ) metabolites in hepatocytes were strongly suppressed by both QN and CQ, perhaps a reflection of the 2D6 inhibition by these drugs. The formation of the carbamoyl glucuronide of PQ (m/z 480) was not affected by CQ/QN.ConclusionThe metabolite-specific interactions in the current studies seem at variance with earlier reports of the dependence of PQ on CYP2D6 metabolism, and enhanced PQ anti-malarial activity/reduced toxicity in the presence of CQ/QN. These results suggest a complex picture in which CQ/QN may shift metabolite pathway balances towards a profile that retains efficacy, while reducing the formation or availability of toxic metabolites to erythrocytes. Alternatively, these drugs may alter transport or distribution of PQ metabolites in a fashion that reduces toxicity while maintaining efficacy against the parasite.

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Enantioselective Pharmacokinetics of Primaquine in Healthy Human Volunteers

Cited by 21 publications

References 43 publications

Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

Differential kinetic profiles and metabolism of primaquine enantiomers by human hepatocytes

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine

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