Human in Vivo Pharmacokinetics of [14C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing

Madeen, Erin; Corley, Richard A.; Crowell, Susan; Turteltaub, Kenneth W.; Ognibene, Ted; Malfatti, Michael; McQuistan, Tammie; Garrard, Mary; Sudakin, Dan; Williams, David E.

doi:10.1021/tx5003996

Cited by 21 publications

(44 citation statements)

References 44 publications

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“…Furthermore, the inherent high sensitivity of the technique allows for studies where high specific activities of radiolabeled compounds are not possible. AMS has been utilized for both rodent and human studies including: nanoparticle dosimetry (Malfatti et al, 2012) and pharmacokinetic and metabolic evaluation of therapeutics and environmental contaminants (Henderson and Pan 2010; Wagner et al, 2011; Malfatti et al, 2014; Madeen et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

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Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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“…19,33–35 To evaluate the accuracy of PBPK model predictions for humans, we performed the first pharmacokinetic study in human volunteers exposed to an ultra-low, but environmentally relevant, oral dose of DBC. 36 Volunteers were orally administered a micro-dose (29 ng) of [ 14 C]-DBC (5 nCi) with plasma and urine analyzed for total [ 14 C] over 72 hours by accelerator mass spectrometry (AMS) at the Lawrence Livermore National Laboratory (LLNL) Center for Mass Spectrometry (CAMS). The 1 mV Bio-AMS provides attomole sensitivity for [ 14 C] electrostatically detected by a particle detector.…”

Section: Introductionmentioning

confidence: 99%

Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

Madeen

Ognibene

Corley

et al. 2016

Chem. Res. Toxicol.

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Metabolism is a key health risk factor for exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in non-smokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (≥4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a micro-dose (29 ng; 5 nCi) of [14C]-DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel “moving wire” interface between ultra-performance liquid chromatography (UPLC) and the AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself, (Cmax= 18.5 ± 15.9 fg/mL, Tmax= 2.1 ± 1.0 h), whereas the major metabolite was identified as [14C]-(+/−)-DBC-11,12-diol (Cmax= 2.5 ± 1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Deconjugated and conjugated metabolites were detected in urine with [14C]-(+/−)-DBC-tetraol identified as the major metabolite, 88.7% of which was detected upon enzymatic deconjugation (Cmax= 35.8 ± 23.0 pg/pool, Tmax= 6–12 h pool). [14C]-DBC-11,12-diol, of which 94.4% was conjugated and identified in urine (Cmax= 29.4 ± 11.6 pg/pool, Tmax= 6–12 h pool). Parent [14C]-DBC was not detected in the urine. This is the first dataset to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose laboratory animal models to human translation for environmental health risk assessment.

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“…The combination of HPLC separation coupled with AMS analysis has allowed for metabolic profiling for such exposures. 5, 78 These approaches have led to the use of AMS to determine the pharmacokinetics and pharmacodynamics of a number of specific agents within humans at physiological doses. 7, 54, 79 Incorporation of these labeled compounds into specific cellular pools has been used to characterize cellular targets and kinetics.…”

Section: Human Studies Enabled By Amsmentioning

confidence: 99%

“…5 Additionally, AMS has been used to characterize the extent of DNA adduct formation in humans after exposure to carcinogenic heterocyclic amines at relevant environmental exposure levels. 83, 84 …”

Section: Human Studies Enabled By Amsmentioning

confidence: 99%

“…5 The pharmacokinetics of DBC was determined in three female and six male human volunteers following an oral microdosing of 14 C -DBC (29 ng, 5 nCi) that was considered of de minimus risk to human health. Following exposure, plasma and urine were collected over 72 h and 14 C-DBC equivalents in plasma and urine were quantified by AMS.…”

Section: Human Studies Enabled By Amsmentioning

confidence: 99%

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Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

Enright¹,

Malfatti²,

Zimmermann

et al. 2016

Chem. Res. Toxicol.

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Accelerator Mass Spectrometry (AMS) has been adopted as a powerful bio-analytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10−18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include: risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy. Combining AMS with complementary capabilities such as high performance liquid chromatography (HPLC) can maximize data within a single experiment and provide additional insight when assessing drugs and toxins, such as metabolic profiling. Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to graphite-based analysis therefore, enabling the use of lower 14C and chemical doses, which are imperative for clinical testing. The aim of this review is to highlight the recent efforts in human studies using AMS, including technological advancements and discussion of the continued promise of AMS for innovative clinical based research.

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Human in Vivo Pharmacokinetics of [¹⁴C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing

Cited by 21 publications

References 44 publications

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

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