The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents
Identifieur interne : 000022 ( Main/Exploration ); précédent : 000021; suivant : 000023The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents
Auteurs : Yuewu Xie ; Huixiang Liu ; Yanhong Sun ; Jie XingSource :
- Malaria Journal [ 1475-2875 ] ; 2020.
Abstract
Naphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated.
The pharmacokinetic profiles of NQ were investigated in healthy male or female rats after a single oral administration of NQ. The antiplasmodial efficacy of NQ was studied in male or female mice infected with
The results showed that the gender of rats did not affect NQ exposure (AUC0–t and Cmax) significantly (
These results indicated that the pharmacokinetic profiles of NQ were similar between male and female rats, except for a longer t1/2 in male rats. The difference was not associated with plasma protein binding or hepatic metabolic clearance. Equivalent antiplasmodial activity was found for NQ in male and female mice infected with
Url:
DOI: 10.1186/s12936-020-3153-8
PubMed: 32054478
PubMed Central: 7020547
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents</title><author><name sortKey="Xie, Yuewu" sort="Xie, Yuewu" uniqKey="Xie Y" first="Yuewu" last="Xie">Yuewu Xie</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liu, Huixiang" sort="Liu, Huixiang" uniqKey="Liu H" first="Huixiang" last="Liu">Huixiang Liu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Sun, Yanhong" sort="Sun, Yanhong" uniqKey="Sun Y" first="Yanhong" last="Sun">Yanhong Sun</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Xing, Jie" sort="Xing, Jie" uniqKey="Xing J" first="Jie" last="Xing">Jie Xing</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32054478</idno><idno type="pmc">7020547</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020547</idno><idno type="RBID">PMC:7020547</idno><idno type="doi">10.1186/s12936-020-3153-8</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000130</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000130</idno><idno type="wicri:Area/Pmc/Curation">000130</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000130</idno><idno type="wicri:Area/Pmc/Checkpoint">000017</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000017</idno><idno type="wicri:Area/Ncbi/Merge">000F26</idno><idno type="wicri:Area/Ncbi/Curation">000F26</idno><idno type="wicri:Area/Ncbi/Checkpoint">000F26</idno><idno type="wicri:Area/Main/Merge">000022</idno><idno type="wicri:Area/Main/Curation">000022</idno><idno type="wicri:Area/Main/Exploration">000022</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents</title><author><name sortKey="Xie, Yuewu" sort="Xie, Yuewu" uniqKey="Xie Y" first="Yuewu" last="Xie">Yuewu Xie</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liu, Huixiang" sort="Liu, Huixiang" uniqKey="Liu H" first="Huixiang" last="Liu">Huixiang Liu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Sun, Yanhong" sort="Sun, Yanhong" uniqKey="Sun Y" first="Yanhong" last="Sun">Yanhong Sun</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Xing, Jie" sort="Xing, Jie" uniqKey="Xing J" first="Jie" last="Xing">Jie Xing</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Malaria Journal</title><idno type="eISSN">1475-2875</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">Naphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated.</p></sec><sec><title>Methods</title><p id="Par2">The pharmacokinetic profiles of NQ were investigated in healthy male or female rats after a single oral administration of NQ. The antiplasmodial efficacy of NQ was studied in male or female mice infected with <italic>Plasmodium yoelii</italic>. The recrudescence and survival time of infected mice were also recorded after drug treatment. Plasma protein binding of NQ was determined in pooled plasma collected from male or female mice, rat or human. In vitro metabolism experiments were performed in the liver microsomes of male or female mice, rat or human.</p></sec><sec><title>Results</title><p id="Par3">The results showed that the gender of rats did not affect NQ exposure (AUC<sub>0–t</sub> and C<sub>max</sub>) significantly (<italic>P </italic>> 0.05). However, a significant (<italic>P </italic>< 0.05) longer t<sub>1/2</sub> was found for NQ in male rats (192.1 ± 47.7), compared with female rats (143.9 ± 27.1). Slightly higher but not significant (<italic>P </italic>> 0.05) antiplasmodial activity was found for NQ in male mice (ED<sub>90</sub>, 1.10 mg/kg) infected with <italic>P. yoelii</italic>, compared with female mice (ED<sub>90</sub>, 1.67 mg/kg). The binding rates of NQ to plasma protein were similar in males and females. There was no metabolic difference for NQ in male and female mice, rat or human liver microsomes.</p></sec><sec><title>Conclusions</title><p id="Par4">These results indicated that the pharmacokinetic profiles of NQ were similar between male and female rats, except for a longer t<sub>1/2</sub> in male rats. The difference was not associated with plasma protein binding or hepatic metabolic clearance. Equivalent antiplasmodial activity was found for NQ in male and female mice infected with <italic>P. yoelii</italic>. 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