Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9

Simonsson, Ulrika S. H.; Jansson, Bjarne; Hai, Trinh Ngoc; Huong, Dinh Xuan; Tybring, Gunnel; Ashton, Michael

doi:10.1016/s0009-9236(03)00092-4

Cited by 96 publications

(68 citation statements)

References 25 publications

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“…The dual hPXR/ hCAR activators ART and CPA also are metabolized by CYP2B6 and/or CYP3A4 (Lindley et al, 2002;Simonsson et al, 2003). Due to induction of CYP3A4 and CYP2B6, these drugs are capable of enhancing their own metabolism (autoinduction), as evidenced by increased clearances and decreased half-lives with multiple dosing compared with single dosing (Bertilsson, 1978;Smith et al, 2001;Simonsson et al, 2003;de Jonge et al, 2005). In addition, these drugs are prescribed frequently in combination with other drugs, leading to drug interactions compromising the efficacy of coadministered therapeutics metabolized by CYP3A4 and CYP2B6 (Spina et al, 1996;Smith et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

Faucette¹,

Zhang²,

Moore³

et al. 2006

J Pharmacol Exp Ther

266

262

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Both the human pregnane X receptor (hPXR) and constitutive androstane receptor (hCAR) are capable of regulating CYP3A4 and CYP2B6 gene expression. However, the majority of currently identified CYP3A4 and CYP2B6 inducers are confirmed activators of hPXR but not hCAR. To compare these receptors with respect to their chemical selectivities, 16 drugs known to induce CYP3A4 and/or CYP2B expression were evaluated for relative activation of hPXR versus hCAR. Because of the high basal but low chemical-induced activation of hCAR in immortalized cells, alternative methods were used to evaluate hCAR activation potential. Thirteen of the 16 compounds were classified as moderate to strong hPXR activators. In contrast, carbamazepine (CMZ), efavirenz (EFV), and nevirapine (NVP) were classified as negligible or weak hPXR activators at concentrations associated with efficacious CYP2B6 reporter or endogenous gene induction in primary human hepatocytes, suggesting potential activation of hCAR. Subsequent experiments demonstrated that these three drugs efficiently induced nuclear accumulation of in vivo-transfected enhanced yellow fluorescent protein-hCAR and significantly increased expression of a CYP2B6 reporter gene when hCAR was expressed in CAR Ϫ/Ϫ mice. In addition, using a recently identified, chemically responsive splice variant of hCAR (hCAR3), the hCAR activation profiles of the 16 compounds were evaluated. By combining results from the hPXR-and hCAR3-based reporter gene assays, these inducers were classified as hPXR, hCAR, or hPXR/hCAR dual activators. Our results demonstrate that CMZ, EFV, and NVP induce CYP2B6 and CYP3A4 preferentially through hCAR and that hCAR3 represents a sensitive tool for in vitro prediction of chemical-mediated human CAR activation.CYP3A4 and CYP2B6 are induced at the mRNA, protein, and activity levels by the same compounds, including rifampin, phenobarbital, clotrimazole, cyclophosphamide, calcium channel antagonists, HMG-CoA reductase inhibitors, and thiazolidinediones (Drocourt et al., 2001;Kocarek et al., 2002;Lindley et al., 2002;Sahi et al., 2003;Faucette et al., 2004). Coinduction of these enzymes is mediated through transcriptional activation of the corresponding genes by the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which are capable of binding to the same response elements in the promoter regions of the CYP3A4 and CYP2B6 genes (Goodwin et al

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Section: Discussionmentioning

confidence: 99%

Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

Faucette¹,

Zhang²,

Moore³

et al. 2006

J Pharmacol Exp Ther

266

262

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“…Time-dependent pharmacokinetics has been well described for artemisinin in healthy subjects and malaria patients (4,10), with a decrease in dose-normalized artemisinin concentrations over 5 days of drug administration due to autoinduction of metabolism (9,25). Declining plasma concentrations for artemether (29) and, less convincingly, for artesunate and dihydroartemisinin (14,35) have been reported following multiple doses.…”

Section: Discussionmentioning

confidence: 99%

First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

Nagelschmitz

Voith

Wensing

et al. 2008

Antimicrob Agents Chemother

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In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10-to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2 ) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2 , its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.Artemisinin and its derivatives, artesunate, artemether, and dihydroartemisinin, are the most potent and rapidly acting antimalarial drugs available today (1, 33). They have very high parasite kill rates with a broad stage specificity of antimalarial action and produce a faster clinical and parasitological response than any other class of antimalarial drug (24,32,33). However, a therapeutic drawback of the artemisinins is the high recrudescence rates associated with monotherapy (6). For artemisinins to be effective when given alone, they must be administered for 7 days, but adherence to 7-day regimens may be poor in patients (34).The latest therapeutic approach to combat both malaria infections and the development of drug resistance has been the use of artemisinin-based combination therapy (ACT) administered over 3 days (1,23,24,34). However, 3-day regimens with the rapidly eliminated artemisinins are usually not curative unless they are given in combination with a slowly eliminated drug, such as mefloquine (34). Although the artemisinins have become the drug of choice for the treatment of multidrug-resistant Plasmodium falciparum malari...

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“…Carbamazepine and artemisinin are examples of CYP3A4 and CYP2B6 substrates and inducers, respectively, that are known to exhibit autoinduction (5,6). Autoinduction is a phenomenon that can occur anytime a drug induces an enzyme which is also predominately involved in its own metabolic clearance.…”

Section: Introductionmentioning

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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Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9

Cited by 96 publications

References 25 publications

Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers

First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

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

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