Dendritic Spine Injury Induced by the 8-Hydroxy Metabolite of Efavirenz

Tovar‐y‐Romo, Luis B.; Bumpus, Namandjé N.; Pomerantz, Daniel; Avery, Lindsay B.; Sacktor, Ned; McArthur, Justin C.; Haughey, Norman J.

doi:10.1124/jpet.112.195701

Cited by 120 publications

(107 citation statements)

References 52 publications

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“…Interestingly, we have shown how there is significant accumulation in the seminal plasma of the hydroxylated metabolites of EFV, which may impact local pharmacology and/or toxicology. Future work may involve examination of the potential for local toxicity in compartments such as the male genital tract, where we have found oxidative metabolites to accumulate, including 8-OH EFV, which has been demonstrated to induce compartment-specific mechanisms of toxicity (Bumpus, 2011;Tovar-Y-Romo et al, 2012). Taken together, this study is the first to demonstrate the anatomic distribution of metabolites of an ARV into relevant biologic compartments and to examine their anti-HIV activity.…”

Section: Discussionmentioning

confidence: 89%

“…Recently, we demonstrated for the first time that 8-OH EFV has the ability to induce cytotoxicity via stimulation of mitochondrial dysfunction and activation of stress-activated signaling pathways (Bumpus, 2011). Subsequently, toxicity of 8-OH EFV to dendritic cells of the CNS has also been reported (Tovar-y-Romo et al, 2012). Although the mechanisms underlying the adverse effects of EFV on semen quality have yet to be fully elucidated, it has been reported that treatment with EFV results in decreased motile spermatozoa and vitality, suggested to be the result of mitochondrial toxicity or direct toxicity to the cells producing spermatozoa (van Leeuwen et al, 2008;Lambert-Niclot et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanisms underlying the adverse effects of EFV on semen quality have yet to be fully elucidated, it has been reported that treatment with EFV results in decreased motile spermatozoa and vitality, suggested to be the result of mitochondrial toxicity or direct toxicity to the cells producing spermatozoa (van Leeuwen et al, 2008;Lambert-Niclot et al, 2011). Because 8-OH EFV has been reported to play a causal role in certain compartment-specific toxicities (Bumpus, 2011;Tovar-y-Romo et al, 2012), understanding the clinical exposure of monohydroxylated and dihydroxylated metabolites of EFV is of importance.…”

Section: Discussionmentioning

confidence: 99%

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Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

et al. 2012

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Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

et al. 2012

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“…In these studies, the most noted adverse events associated with the efavirenz-containing regimen were psychiatric symptoms and rash; however, the molecular mechanism(s) that underlie the differences in the safety profiles of RPVcontaining versus efavirenz-containing regimens is unknown (6,7). While we recently demonstrated that the primary metabolite of efavirenz, 8-hydroxyefavirenz, may play a causal role in efavirenz-mediated toxicities, including hepatic and neuronal toxicity, this type of analysis is not yet possible for RPV, as the metabolites of this drug have yet to be defined (8,9).…”

Section: R Ilpivirine (Rpv; Edurant) 4-[[4-[[4-[(1e)-2-cyanoethenyl]mentioning

confidence: 99%

Human Biotransformation of the Nonnucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross-Species Metabolism Comparison

Lade

Avery

Bumpus

2013

Antimicrob Agents Chemother

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Rilpivirine is a nonnucleoside reverse transcriptase inhibitor used to treat HIV-1. In the present study, the pathways responsible for the biotransformation of rilpivirine were defined. Using human liver microsomes, the formation of two mono-and two dioxygenated metabolites were detected via ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Mass spectral analysis of the products suggested that these metabolites resulted from oxygenation of the 2,6-dimethylphenyl ring and methyl groups of rilpivirine. Chemical inhibition studies and cDNA-expressed cytochrome P450 (CYP) assays indicated that oxygenations were catalyzed primarily by CYP3A4 and CYP3A5. Glucuronide conjugates of rilpivirine and a monomethylhydroxylated metabolite of rilpivirine were also detected and were found to be formed by UDP-glucuronosyltransferases (UGTs) UGT1A4 and UGT1A1, respectively. All metabolites that were identified in vitro were detectable in vivo. Further, targeted UHPLC-MS/MS-based in vivo metabolomics screening revealed that rilpivirine treatment versus efavirenz treatment may result in differential levels of endogenous metabolites, including tyrosine, homocysteine, and adenosine. Rilpivirine biotransformation was also assessed across species using liver microsomes isolated from a range of mammals, and the metabolite profile identified using human liver microsomes was largely conserved for both oxidative and glucuronide metabolite formation. These studies provide novel insight into the metabolism of rilpivirine and the potential differential effects of rilpivirine-and efavirenz-containing antiretroviral regimens on the endogenous metabolome.benzonitrile, is a more recently developed nonnucleoside reverse transcriptase inhibitor that has been FDA approved for oral administration in combination therapy for the treatment of drug-naive individuals infected with human immunodeficiency virus 1 (HIV-1) (1). RPV is a cyanovinyl diarylpyrimidine and as such has inherent molecular flexibility, allowing for multiple modes of allosteric binding within the hydrophobic binding pocket of the HIV reverse transcriptase; therefore, RPV has a higher genetic barriertoresistancethantheinitiallydevelopednonnucleosidereversetranscriptaseinhibitors,efavirenzandnevirapine(2,3).Inaddition,becauseof its antiviral efficacy, RPV is being developed as an injectable, long-acting formulation for potential use in HIV preexposure prophylaxis (4, 5). ECHO and THRIVE clinical trials, comparing RPV-tenofoviremtricitabine (Complera) treatment to that with efavirenz-tenofoviremtricitabine (Atripla), demonstrated that the RPV coformulation has more potent antiviral activity and fewer adverse side effects than does a daily antiretroviral efavirenz-based regimen. In these studies, the most noted adverse events associated with the efavirenz-containing regimen were psychiatric symptoms and rash; however, the molecular mechanism(s) that underlie the differences in the safety profiles of RPVcontaining versus efavirenz-containing regimens is u...

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“…Furthermore, there are secondary metabolites associated with products of primary metabolism [4,5]. A relatively fewer number of studies have attempted to link efavirenz induced CNS toxicity with 8-hydroxefavirenz [6,7]. A possible metabolites movement carrier in a patient who had been on efavirenz is suggested.…”

Section: Introductionmentioning

confidence: 99%

Derived wave of gradient driven diffusion's convective flux of efavirenz

Nemaura

2018

J. Phys. Commun.

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Dendritic Spine Injury Induced by the 8-Hydroxy Metabolite of Efavirenz

Cited by 120 publications

References 52 publications

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

Human Biotransformation of the Nonnucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross-Species Metabolism Comparison

Derived wave of gradient driven diffusion's convective flux of efavirenz

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