53 research outputs found
Attenuation of Acute Rejection in a Rat Liver Transplantation Model by a Liver-Targeted Dextran Prodrug of Methylprednisolone
The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in non-target tissues. Therefore, selective delivery of MP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model
Targeted Metabolomic Approach for Assessing Human Synthetic Cannabinoid Exposure and Pharmacology
Designer
synthetic cannabinoids like JWH-018 and AM2201 have unique
clinical toxicity. Cytochrome-P450-mediated metabolism of each leads
to the generation of pharmacologically active (ω)- and (ω-1)-monohydroxyl
metabolites that retain high affinity for cannabinoid type-1 receptors,
exhibit Δ<sup>9</sup>-THC-like effects in rodents, and are conjugated
with glucuronic acid prior to excretion in human urine. Previous studies
have not measured the contribution of the specific (ω-1)-monohydroxyl
enantiomers in human metabolism and toxicity. This study uses a chiral
liquid chromatography–tandem mass spectroscopy approach (LC–MS/MS)
to quantify each specific enantiomer and other nonchiral, human metabolites
of JWH-018 and AM2201 in human urine. The accuracy (average % RE =
18.6) and reproducibility (average CV = 15.8%) of the method resulted
in low-level quantification (average LLQ = 0.99 ng/mL) of each metabolite.
Comparisons with a previously validated nonchiral method showed strong
correlation between the two approaches (average <i>r</i><sup>2</sup> = 0.89). Pilot data from human urine samples demonstrate
enantiospecific excretion patterns. The (<i>S</i>)-isomer
of the JWH-018-(ω-1)-monohydroxyl metabolite was predominantly
excreted (>87%) in human urine as the glucuronic acid conjugate,
whereas
the relative abundance of the corresponding AM2201-(ω-1)-metabolite
was low (<5%) and did not demonstrate enantiospecificity (approximate
50:50 ratio of each enantiomer). The new chiral method provides a
comprehensive, targeted metabolomic approach for studying the human
metabolism of JWH-018 and AM2201. Preliminary evaluations of specific
enantiomeric contributions support the use of this approach in future
studies designed to understand the pharmacokinetic properties of JWH-018
and/or AM2201
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