Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects

Asimus, Sara; Elsherbiny, Doaa A.; Hai, Trinh Ngoc; Jansson, Bjarne; Huong, Nguyen Van; Petzold, Max; Simonsson, Ulrika S. H.; Ashton, Michael

doi:10.1111/j.1472-8206.2007.00471.x

Cited by 72 publications

(47 citation statements)

References 33 publications

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“…Choice of substrates is important as they need to be CYP specific with no interactions between any of the substrates in the cocktail. A recent study by Asimus et al (53), investigated the effect of the antimalarial drug artemisinin and its derivatives on the major human CYP enzymes. Asimus et al designed a six drug cocktail study consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam to assess CYP1A2, 2A6, 2C19, 2D6, 2E1 and 3A4 activity, respectively.…”

Section: Clinical Drug Interaction Studiesmentioning

confidence: 99%

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Sinz

Wallace

Sahi³

2008

AAPS J

114

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Abstract. Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions.

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Section: Clinical Drug Interaction Studiesmentioning

confidence: 99%

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Sinz

Wallace

Sahi³

2008

AAPS J

114

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“…In addition to the autoinduction phenomenon, both QHS and DHA were found to be potent inhibitors of CYP1A2 activity in vitro (Bapiro et al, 2001) and in vivo (Bapiro et al, 2005;Asimus et al, 2007). Taken together, these results showed that QHS drugs may affect cytochrome P450s (P450s) as both inducer and inhibitor, which may compromise the results of P450 activity in vivo.…”

Section: Introductionmentioning

confidence: 68%

“…QHS appears to induce other enzymes including CYP2C19 (Svensson et al, 1998;Mihara et al, 1999; omeprazole as a marker), CYP3A4 (midazolam hydroxylation; Asimus et al, 2007), CYP2A6 (coumarin hydroxylation; Asimus et al, 2008), and glucuronidation (7-hydroxycoumarin glucuronidation; Asimus et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes

et al. 2012

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ABSTRACT:Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K i 4.6 M), but not CYP3A4 (IC 50 ϳ 50 M) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC 50 > 125 M). In addition, it was found that QHS induced the activity of CYP3A4 (E max 3.5-fold and EC 50 5.9 M) and CYP2B6 (E max 1.9-fold and EC 50 0.6 M). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E max 7.9-fold and EC 50 5.2 M) and CYP2A6 (E max 11.7-fold and EC 50 4.0 M) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUC i /AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.

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“…A previously performed in vivo study including 75 Vietnamese subjects showed a significant interindividual variation in the degree of artemisinin-driven induction of several CYP450 enzymes, including CYP3As, the genes which are canonical targets of PXR (1). In the present work, we built upon this study by hypothesizing that specific single nucleotide polymorphisms (SNPs) in PXR might explain the observed interindividual variability in the level of CYP3A induction.…”

mentioning

confidence: 99%

PXR Variants and Artemisinin Use in Vietnamese Subjects: Frequency Distribution and Impact on the Interindividual Variability of CYP3A Induction by Artemisinin

Piedade

Schaeffeler

Winter

et al. 2012

Antimicrob Agents Chemother

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f Artemisinins induce drug metabolism through the activation of the pregnane X receptor (PXR) in vitro. Here, we report the resequencing and genotyping of PXR variants in 75 Vietnamese individuals previously characterized for CYP3A enzyme activity after artemisinin exposure. We identified a total of 31 PXR variants, including 5 novel single nucleotide polymorphisms (SNPs), and we identified significantly different allele frequencies relative to other ethnic groups. A trend of significance was observed between the level of CYP3A4 induction by artemisinin and two PXR variants, the 8118C¡T (Y328Y) and 10719A¡G variants.A rtemisinin combination therapy (ACT) is an integral part of the global management of malaria (7). In this treatment strategy, an artemisinin-related compound with a short half-life (t 1/2 ; ϳ0.25 to 4 h) is combined with a more slowly eliminated antimalarial to reduce recrudescence and to slow the development of resistance (24). Currently, several ACT formulations, including artesunate-mefloquine, artemether-lumefantrine, and artesunate-amodiaquine, are used (27), and a second generation of ACTs is being scheduled for global launch. These ACTs include dihydroartemisinin-piperaquine (5) and artesunate-pyronaridine (30).In vitro studies indicate that artemisinin, arteether, and artemether are effective ligands of the pregnane X receptor (PXR) (4), a nuclear receptor and a key player in the regulation of the expression of proteins involved in drug metabolism (e.g., cytochrome P450s [CYP450s]) and transport (e.g., ABC transporters) (6). Variability in the expression and function of these proteins may lead to alterations in the pharmacokinetics of artemisinin derivatives, possibly resulting in pharmacodynamic changes and subsequent clinical consequences such as side effects (14).A previously performed in vivo study including 75 Vietnamese subjects showed a significant interindividual variation in the degree of artemisinin-driven induction of several CYP450 enzymes, including CYP3As, the genes which are canonical targets of PXR (1). In the present work, we built upon this study by hypothesizing that specific single nucleotide polymorphisms (SNPs) in PXR might explain the observed interindividual variability in the level of CYP3A induction. For this purpose, the PXR gene was fully resequenced in all individuals who participated in the study mentioned above, with a focus on the open reading frame (ORF) (mutations in which could lead to proteins with altered activities), intron-exon boundaries (mutations in which could lead to disturbances in the well-documented alternative splicing of PXR), and the proximal promoter (mutations in which could modulate basal expression). Additionally, known variants with putative functional consequences located in introns and other regions (e.g., the 3= region) were genotyped by using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology. Primers and amplification conditions are listed in Table S1 in the supplemental material....

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Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects

Cited by 72 publications

References 33 publications

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Evaluation of P450 Inhibition and Induction by Artemisinin Antimalarials in Human Liver Microsomes and Primary Human Hepatocytes

PXR Variants and Artemisinin Use in Vietnamese Subjects: Frequency Distribution and Impact on the Interindividual Variability of CYP3A Induction by Artemisinin

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