Glucuronidation of Dihydroartemisinin in Vivo and by Human Liver Microsomes and Expressed UDP-Glucuronosyltransferases

Ilett, Kenneth F.; Ethell, Brian T.; Maggs, James L.; Davis, Timothy; Batty, Kevin T.; Burchell, Brian; Bình, Trần Quang; Thư, Le Thi Anh; Hung, Nguyen Canh; Pirmohamed, Munir; Park, B. Kevin; Edwards, Geoffrey

doi:10.1124/dmd.30.9.1005

Cited by 136 publications

(105 citation statements)

References 34 publications

(30 reference statements)

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“…Artemisinin-based combination therapies, including those with DHA, are viewed as the most promising drug strategies for combating malaria-related morbidity and mortality [8,9]. In Vietnamese adult malaria patients given artesunate, α-DHA-β-glucuronide was found to be the major urinary product of DHA glucuronidation, and, using V79 cells expressing human UGT1A1, 1A6, 1A9, or 2B7, α-DHA-β-glucuronide formation was observed with UGT1A9 and UGT2B7, but not with UGT1A1 and UGT1A6 [4].…”

Section: Introductionmentioning

confidence: 99%

“…Using HEK293 cells expressing human UGT2B4, 2B7, 2B10, 2B11, 2B15, or 2B17, it was observed that only UGT2B7 catalyzed the formation of AZT-glucuronide [10]. The DHA glucuronidation [4] and AZT glucuronidation [10] studies were not performed with all 18 known human UGTs, and it is possible that other UGTs might be important for the glucuronidation of these anti-infectious drugs. Although efavirenz and its phase I hydroxyl metabolites [11] and phase I hydroxyl metabolites of nevirapine [12] have been shown to undergo glucuronidation, indicating the involvement of phase II pathway through UGTs, there is currently no information, to our knowledge, on the identity of the UGT involved in the glucuronidation of these commonly prescribed antiretroviral drugs.…”

Section: Introductionmentioning

confidence: 99%

“…In humans, UGT1A9 and UGT2B7 catalyze glucuronidation of dihydroartemisinin (DHA), which belongs to a novel class of highly effective antimalarials called artemisinin drugs [4]. Dihydroartemisinin is a derivative of the parent compound artemisinin and the major metabolite of artemisinin derivatives artesunate, artemether, β-arteether, and artelinic acid [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

Mehlotra

Bockarie

Zimmerman

2006

Eur J Clin Pharmacol

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Objective-UDP-glucuronosyltransferases (UGTs) UGT1A9 and UGT2B7 are involved in the metabolism of antimalarial dihydroartemisinin and antiretroviral zidovudine. Our aim was to analyze the prevalence of UGT1A9 (chromosome 2) and UGT2B7 (chromosome 4) nonsynonymous single nucleotide polymorphisms (SNPs) in West African (WA), Papua New Guinean (PNG), and North American (NA) populations.Methods-Using a post-PCR ligation detection reaction-fluorescent microsphere assay, frequencies of UGT1A9 (8G>A, 98T>C, 766G>A) and UGT2B7 (211G>T, 802C>T, 1192G>A) SNPs were determined in WA (n=133, 5 countries), PNG (n=153), and NA (n=350, 4 ethnic groups) individuals.Results-The UGT1A9 variant alleles were not common in the study populations. None of the SNPs were present in WA and PNG. Among NA, all 3 SNPs were present (1% each) in AsianAmericans, while 98T>C was present only in Caucasian-Americans (1%) and Hispanic-Americans (1%). Regarding UGT2B7 SNPs, the prevalence of 802C>T was 21% in WA, 28% in PNG, and 28-; 52% in NA. The SNP 211G>T was present only in Asian-Americans (9%) and Hispanic-Americans (2%), while 1192G>A was not present in any of the subjects. No significant linkage was observed at UGT1A9, UGT2B7, and between both the loci in any of the study populations.Conclusions-Taken together, the UGT1A9-UGT2B7 polymorphism profile in WA and PNG populations is similar to African-Americans, but different from Asian-Americans. It is important to determine if these differences, along with previously reported differences in cytochrome P450 2B6 allele frequencies, are associated with altered metabolism/ effectiveness of artemisinin drugs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

Mehlotra

Bockarie

Zimmerman

2006

Eur J Clin Pharmacol

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“…In this regard, AS is known to be completely hydrolyzed in the blood by tissue cholinesterases to yield its active metabolite, DHA, 38 and DHA is further conjugated by the UDP-glucuronosyltransferase system. 39 In addition, AS has been reported to be metabolized by CYP450. In this regard, CYP2A6 has been found to be the major metabolizing enzyme for AS.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

Matar

Awad

Elamin

2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, T max values of AS and DHA were significantly prolonged in the combination group (P 0.05). However, there was no significant effect on the other pharmacokinetic parameters (P 0.05). The t 1/2 values of AS and DHA were significantly higher in females than in males (P 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.

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“…Similar to AS, no notable change was observed in the pharmacokinetic parameters of DHA in DM rats, whereas the AUC of blood was slightly increased in DM (Figure 2 and Table 3). After its conversion from AS, DHA is not oxidized by cytochrome-P450, but is glucuronidated by the UDP-glucuronosyltransferases 1A9 and 2B7 (UGT1A9 and UGT2B7) in the liver [28,29]. Dostalek et al, investigated the effect of DM on glucuronidation by UGT1A9 and UGT2B7 in the human liver and showed that the expression and activity of UGT2B7, but not of UGT1A9, were significantly decreased in DM [30]; however, the effect of DM on DHA disposition was not significant in rats in the present study.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

Fukushima¹,

Uchimura²,

Okada³

et al. 2014

Interact Med Chem

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Background: Artesunate (AS), an anti-malarial drug, is hydrolyzed by serum esterase for its conversion to the active metabolite, dihydroartemisinin (DHA). Evidence for the clinical effectiveness of AS is growing; however, little information is available on special populations such as patients with diabetes mellitus (DM). In addition, although erythrocytes are considered as a target site, the blood pharmacokinetics of AS and DHA remain unclear. Therefore, the blood pharmacokinetics of AS and DHA were investigated in DM rats in the present study. Methods: DM rats were prepared by intraperitoneal injection of streptozotocin. An in vitro protein binding study of AS and DHA was performed by the ultrafiltration method. Plasma and blood samples were collected after the intravenous administration of AS, to analyze pharmacokinetics of AS and DHA. Blood to plasma ratios (BP ratio), as an index of erythrocyte distribution, were then calculated by dividing blood concentrations by plasma concentrations. Results: The protein bindings of AS and DHA were 83.7% and 92.6% in control rats and 86.2% and 92.2% in DM rats, respectively. All concentration profiles in this study were best fit by a two compartment model; the plasma and blood pharmacokinetic parameters of AS and DHA in DM rats were not significantly different from those in control rats. The BP ratio of AS was at an extremely low level (approximately 0.5) just after its administration, whereas that of DHA was maintained above 1.0 throughout the study; however, no significant changes were observed between control and DM rats. Conclusion:The glycation of albumin with DM did not affect the protein bindings of AS or DHA. No significant changes were observed in the conversion of AS to DHA by serum esterase or disposition of DHA in DM rats. The blood concentrations of DHA declined in parallel with plasma concentrations and the distribution of DHA to erythrocytes was good. In conclusion, the efficacy and safety of both AS and DHA were tolerated in DM rats with DHA having more favorable characteristics than AS.

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Glucuronidation of Dihydroartemisinin in Vivo and by Human Liver Microsomes and Expressed UDP-Glucuronosyltransferases

Cited by 136 publications

References 34 publications

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

Prevalence of UGT1A9 and UGT2B7 nonsynonymous single nucleotide polymorphisms in West African, Papua New Guinean, and North American populations

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

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