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- Gordi, T, et al.
(författare)
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A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction
- 2005
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Ingår i: Br J Clin Pharmacol.. ; 59:2, s. 189-98
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Previous studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of artemisinin in healthy subjects. METHODS: Twenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two-compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction. RESULTS: Artemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half-life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non-linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first-pass extraction. CONCLUSION: Artemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the time-course of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.
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| 2. |
- Asimus, Sara, 1976, et al.
(författare)
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Artemisinin and CYP2A6 activity in healthy subjects.
- 2007
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 64:3, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6. METHODS: Twelve healthy male Vietnamese subjects were given coumarin or nicotine in randomized sequence before and after 5 days of a repeated oral administration of artemisinin during two different treatment periods 1 month apart. Sequential blood samples were drawn at baseline 7 days prior to artemisinin treatment and on the first and fifth day of artemisinin treatment during both treatment periods. Plasma concentrations of 7-hydroxycoumarin glucuronide (7-OHCG), nicotine, cotinine and artemisinin were analysed by high-performance liquid chromatography and those of coumarin and 7-hydroxycoumarin (7-OHC) were determined by liquid chromatography-tandem mass spectrometry. Urine, collected in two time intervals on the days of coumarin intake, was treated with beta-glucuronidase and analysed for 7-OHC levels. RESULTS: Artemisinin [Formula: see text] values decreased significantly to 23% [95% confidence interval (CI) 18%-28%] on the fifth day of artemisinin administration as compared with the first. The sum of renally excreted 7-OHC and 7-OHCG increased by 1.55-fold (adjusted 95% CI 1.08-2.23) in the 3- to 8-h interval compared to baseline 7 days before. The 7-OHCG/7-OHC plasma [Formula: see text] ratio increased by 1.72-fold (adjusted 95% CI 1.16-2.54) following 5 days of artemisinin intake. There was no significant change in the cotinine/nicotine AUC(0-11 hr) ratio between study days. CONCLUSION: Artemisinin significantly increased the sum of renally excreted 7-OHC and 7-OHCG in one of the two collection intervals, suggesting an induction of CYP2A6. A significant increase in the 7-OHCG to 7-OHC [Formula: see text] ratio indicates artemisinin to be an inducer of glucuronidation.
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