Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto‐induction in the rat by use of nonlinear mixed effects modelling

Svensson, U; Mäki-Jouppila, Mika; Hoffmann, Kurt‐Jürgen; Ashton, Michael

doi:10.1002/bdd.342

Cited by 22 publications

(15 citation statements)

References 11 publications

(20 reference statements)

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“…However, the induction of the metabolic clearance of ARTS or DHA is less likely in our view because their metabolic pathways (hydrolysis [26] and glucuronidation [19], respectively) are unlikely to change acutely. Nevertheless, there is clear evidence for the induction of ARTS metabolism during repeated administration of an oral or rectal dose (18,42), largely as a result of CYP2B6 induction (36).…”

Section: Discussionmentioning

confidence: 99%

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Karunajeewa

Ilett

Dufall³

et al. 2004

Antimicrob Agents Chemother

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A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and ␣-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

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Section: Discussionmentioning

confidence: 99%

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Karunajeewa

Ilett

Dufall³

et al. 2004

Antimicrob Agents Chemother

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“…However, since depletion data reflect the sum of activity of all potential microsomal enzymes involved, characterization of artemisinin metabolites would be required in order to evaluate and validate it as a possible specific CYP2B6 probe. Nevertheless it was found that when incubating human liver microsomes with 14 C-labelled artemisinin three radiolabelled products were formed [25]. By discrimination of different models applied to the observed rates of metabolism and metabolite formation it was concluded that two primary and one secondary metabolite were formed.…”

Section: Discussionmentioning

confidence: 98%

Artemisinin–a possible CYP2B6 probe substrate?

Asimus

Ashton

2009

Biopharm & Drug Disp

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The rate of in vitro metabolism of artemisinin was correlated significantly to that of bupropion, propofol and efavirenz, suggesting artemisinin to be a potential alternative marker to assess CYP2B6 activity. Further studies characterizing the metabolic fate of artemisinin are needed in order to evaluate its utility as an in vitro and in vivo CYP2B6 probe substrate, since CYP2B6 might not be the only CYP isoform involved in the depletion of artemisinin.

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“…Dihydroartemisinin (DHA) is a reduced product of artemisinin and it is the primary metabolite of artemisinin and its derivatives [38]. DHA is water soluble, relatively unstable and very prone to oxidative reactions because of the lactol moeity in its structure.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Antioxidant Status and Biochemical Indices Following Administration of Dihydroartemisinin-Piperaquine Phosphate (P-ALAXIN® )

Olayinka¹

2013

IOSR-JPBS

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Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto‐induction in the rat by use of nonlinear mixed effects modelling

Cited by 22 publications

References 11 publications

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Artemisinin–a possible CYP2B6 probe substrate?

Alterations in Antioxidant Status and Biochemical Indices Following Administration of Dihydroartemisinin-Piperaquine Phosphate (P-ALAXIN® )

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