Artemisinin induces omeprazole metabolism in human beings*

Svensson, U; Ashton, Michael; Hai, Trinh Ngoc; Bertilsson, Leif; Huong, Dinh Xuan; Huong, Nguyen Van; Niêu, Nguyen Thi; Sy, Nguyen Duy; Lykkesfeldt, Jens; Cong, Le

doi:10.1016/s0009-9236(98)90149-7

Cited by 81 publications

(75 citation statements)

References 12 publications

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“…Although this study sampled blood to 24 h postdose, ART could be quantified in samples only up to 8 h. The present median AUC 0 -ϱ of the first dose of ART (1,347 g · h/liter) was within the range reported for healthy adults (1,190 to 2,690 g · h/liter) (6,7,10,19,43) but well below that of adults with malaria (2,601 to 2,780 g · h/liter) (2, 9, 26) who received 500 mg of ART. Our children received a lower dose of ART (3.2 mg/kg/day), and, when adjusted for the relative dose administered, the AUC 0 -ϱ for the first dose was above those seen in adults (2,9,26).…”

Section: Discussionsupporting

confidence: 60%

“…In comparisons of the AUCs of different doses in previous studies, the relative bioavailability after 4 to 7 days was between 0.13 and 0.29 (7,9,22,26,40,43). One study of African adults with malaria who received 500 mg of ART daily for 3 days and a single dose of mefloquine (42) measured ART in saliva and found that relative bioavailability was lower (0.45) only on the third day when mefloquine was given after the last dose of ART.…”

Section: Discussionmentioning

confidence: 94%

“…A number of published studies have evaluated the pharmacokinetics of ART in healthy adults (6,7,10,19,23,43) and adults with malaria (2,9,21,22,24,26,42), but only one has included children with malaria (40). In the latter Vietnamese study, 23 children aged 2 to 12 years were given 5 days of ART dosed according to body weight (approximately 10 mg) and 31 adults received 500 mg of ART daily for 5 days.…”

Section: Discussionmentioning

confidence: 99%

“…The elimination t 1/2 of ART has been reported to be between 1.4 and 4.8 h in noncompartmental (2,6,7,9,21,22,26,42,43) and compartmental (10,19,23,24,40) analyses. The present analysis supports a biexponential disposition for ART, while most previous compartmental analyses have reported a monoexponential disposition.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

Salman

Page‐Sharp

Batty

et al. 2012

Antimicrob Agents Chemother

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Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC 0 -ؕ ), with medians of 49,451 (n ‫؍‬ 12) and 44,556 (n ‫؍‬ 22) g · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC 0 -ؕ was 1,652 g · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.T he most recent World Health Organization (WHO) recommendations for the treatment of uncomplicated malaria include a 3-day course of dihydroartemisinin plus piperaquine (DHA-PQ) as a first-line artemisinin (ART) combination therapy (ACT) (48). Various formulations of DHA-PQ are marketed in tropical countries (Duo-cotecxin, Combimal, and P-Alaxin; http://www.actwatch.info /resources/drugs_home03_search.asp) or are in development (Eurartesim) (20), and all employ PQ tetraphosphate as the DHA partner drug. DHA is a semisynthetic derivative of ART, and its production adds to the manufacturing cost, but, unlike ART, it does not exhibit autoinduction of metabolism. In addition, although the tetraphosphate salt of PQ has greater water solubility and therefore may have better oral bioavailability, incorporation of the lipid-soluble PQ base should also simplify production.Artequick (Artepharm Co. Ltd., Guangzhou, China) is an ACT that contains ART in place of DHA and PQ base rather than PQ tetraphosphate. This combination is formulated as tablets but also as granules for pediatric use. It is marketed in ...

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

Salman

Page‐Sharp

Batty

et al. 2012

Antimicrob Agents Chemother

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“…Our results suggest a significant effect of sex on the kinetics of the drug on the first treatment day, with higher CL s /F values for female patients. Artemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6, with a probable secondary contribution of CYP3A4 in individuals with low levels of CYP2B6 expression (23). Reports on differences in the activities of these enzymes by sex are scarce, although indications of higher levels of activity in female subjects have been reported for CYP2A6 (11,20).…”

Section: Discussionmentioning

confidence: 99%

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Gordi

Huong

Hai

et al. 2002

Antimicrob Agents Chemother

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The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n ‫؍‬ 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n ‫؍‬ 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ؎ standard deviations, 50 ؎ 23 and 34 ؎ 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P ‫؍‬ 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose-and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.Artemisinin and its semisynthetic family of derivatives are the most potent antimalarials available for treatment of falciparum malaria infections (15,25,26). Artemisinin has a short elimination half-life, a rapid onset of action, no major side effects, and markedly induces of its own metabolic elimination, resulting in five-to sevenfold decreases in its concentrations over 5 to 7 days of administration in both malaria patients and healthy subjects (1, 3-5). A major drawback with artemisinin and its derivatives is the high recrudescence rates within 2 to 3 weeks after monotherapy (14,17). It has proved difficult in field studies to determine whether the relapsed malaria episodes are due to new infections or the persistence of the previous one. However, true recrudescence has been described in patients kept in vector-free environments for longer periods of time (12,13,16). There is also evidence of true recrudescence, as determined by a PCR technique with patients treated with a combination of artemether and benflumetol (10) as well as artesunate alone (18). It has been suggested that the occurrence of recrudescence may partly be due to the decreasing artemisinin concentrations toward the end of treatment (4). Thus, the time-dependent kinetics of the drug can be of importance in dosing suggestions.Reports concerning dose-response studies with the artemisinin endoperoxides are lacking. Rectal administration of artemisinin was shown to have efficacy comparable to that of oral treatment in terms of the parasite clearance time (PCT) and the fever subsidence time (FST) in patients with uncomplicated falciparum mal...

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Discovery of Antimalarial Drug Artemisinin and Beyond

Mao¹,

Zhang²

2012

Case Studies in Modern Drug Discovery and Development

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Artemisinin induces omeprazole metabolism in human beings*

Abstract: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.

Cited by 81 publications

References 12 publications

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Discovery of Antimalarial Drug Artemisinin and Beyond

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