Toxicokinetics of new psychoactive substances: plasma protein binding, metabolic stability, and human phase I metabolism of the synthetic cannabinoid WIN 55,212-2 studied usingin vitrotools and LC-HR-MS/MS

2016 ◽  
Vol 8 (10) ◽  
pp. 1039-1048 ◽  
Author(s):  
Marie Mardal ◽  
Emma Gracia-Lor ◽  
Svenja Leibnitz ◽  
Sara Castiglioni ◽  
Markus R. Meyer
Keyword(s):  
Protein Binding ◽  
Phase I ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Synthetic Cannabinoid ◽  
Metabolic Stability ◽  
New Psychoactive Substances ◽  
Psychoactive Substances ◽  
Phase I Metabolism

Toxicokinetic Studies and Analytical Toxicology of the New Synthetic Opioids Cyclopentanoyl-Fentanyl and Tetrahydrofuranoyl-Fentanyl

2020 ◽  
Vol 44 (5) ◽  
pp. 449-460 ◽  
Author(s):  
Tanja M Gampfer ◽  
Lea Wagmann ◽  
Matthias J Richter ◽  
Svenja Fischmann ◽  
Folker Westphal ◽  
...  
Keyword(s):  
Protein Binding ◽  
Phase I ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
New Psychoactive Substances ◽  
Analytical Toxicology ◽  
Rat Urine ◽  
Analytical Strategy ◽  
Synthetic Opioids

Abstract The growing number of new synthetic opioids (NSO) on the new psychoactive substances (NPS) market bears new challenges in toxicology. As their toxicodynamics and particularly their toxicokinetics are usually unknown, impact on human health is not yet fully understood. Detection of the 2 NSO cyclopentanoyl-fentanyl (CP-F) and tetrahydrofuranoyl-fentanyl (THF-F) was first reported in 2016. Both were involved in several fatal intoxication cases, but no detailed information about their toxicological characteristics is available so far. The main purpose of this study was therefore to investigate the in vitro toxicokinetics and in vivo analytical toxicology of CP-F and THF-F by means of liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). These studies included metabolic stability, phase I and II metabolism, isozyme mapping, plasma protein binding and detectability in LC-HRMS/MS standard urine screening approaches (SUSA) using rat urine samples. In total, 12 phase I metabolites of CP-F and 13 of THF-F were identified, among them 9 metabolites described for the first time. Overall, N-dealkylations, hydroxylations and dihydroxylations were the main metabolic reactions. The cytochrome P450 (CYP) isozymes mainly involved were CYP2D6 and CYP3A4, leading to elevated drug levels and intoxications in CYP2D6 poor metabolizers. CP-F showed a high plasma protein binding of 99%, which may increase the risk of toxicity by simultaneous intake of other highly bound drugs. Detectability studies showed that neither the parent compounds nor their metabolites were detectable in rat urine using LC-HRMS/MS SUSA. However, a more sophisticated analytical strategy was successfully applied and should be used for analytical confirmation of an intake of CP-F and/or THF-F.

Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms

2001 ◽  
Vol 19 (8) ◽  
pp. 2319-2333 ◽  
Author(s):  
Edward A. Sausville ◽  
Susan G. Arbuck ◽  
Richard Messmann ◽  
Donna Headlee ◽  
Kenneth S. Bauer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Protein Binding ◽  
Phase I ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Large Cell ◽  
Maximum Tolerated Dose

PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m2/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m2/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m2/d for 3 days included mean total plasma concentration of 36.4 μM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G2 checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

2019 ◽  
Vol 11 (6) ◽  
pp. 886-897 ◽  
Author(s):  
Bahia A. Moussa ◽  
Asmaa A. El‐Zaher ◽  
Mohamed K. El‐Ashrey ◽  
Marwa A. Fouad
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Pharmacokinetic Profile ◽  
Metabolic Stability

Bioavailability, plasma protein binding and metabolic stability studies of a ALDH2 activator, alda-1, using a validated LC-ESI-MS/MS method in rat plasma

RSC Advances ◽  
2015 ◽  
Vol 5 (67) ◽  
pp. 54395-54402 ◽  
Author(s):  
Isha Taneja ◽  
Kanumuri Siva Rama Raju ◽  
Monika Mittal ◽  
Kapil Dev ◽  
Mohammad Faheem Khan ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Rat Plasma ◽  
Metabolic Stability ◽  
Stability Studies ◽  
Esi Ms

Alda-1 was found to be a poorly bioavailable, 82–86% protein bound, high extraction compound.

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