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Metabolism and Disposition of Dasatinib after Oral Administration to Humans
TLDR
The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC50 for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity. Expand
Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics
TLDR
Multiple in vitro experiments showed that dasatinib was predominately metabolized by CYP3A4, and suggested that the formation of M20 was more efficient than other metabolites. Expand
Biotransformation of [14C]Dasatinib: In Vitro Studies in Rat, Monkey, and Human and Disposition after Administration to Rats and Monkeys
TLDR
Across species, dasatinib underwent in vitro oxidative metabolism to form five primary oxidative metabolites and secondary metabolites formed from combinations of the oxidative pathways and conjugated metabolites of dAsatinib and its oxidative metabolites were also observed in hepatocytes incubations. Expand
Cysteine Conjugate beta‐Lyase‐Dependent Metabolism of Compound A (2‐[fluoromethoxy]‐1,1,3,3,3‐pentafluoro‐1‐propene) in Human Subjects Anesthetized with Sevoflurane and in Rats Given Compound A
TLDR
The formation of compound A‐derived mercapturates shows that compound A undergoes glutathione S‐conjugate formation and the identification of 2‐(fluoromethoxy)‐3,3, 3‐trifluoropropanoic acid in the urine of humans anesthetized with sevoflurane shows that compounds A underwentes beta‐lyase‐dependent metabolism. Expand
Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper
TLDR
This white paper contains observations from the ADC ADME working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs. Expand
Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro
TLDR
DF-AG is unstable in plasma and undergoes conversion to parent DF, so caution is warranted when assessing renal and hepatic transporter-mediated drug-drug interactions with DF and DF-AG. Expand
In Vitro and In Vivo Metabolism and Pharmacokinetics of BMS-562086, a Potent and Orally Bioavailable Corticotropin-Releasing Factor-1 Receptor Antagonist
TLDR
Virtual clinical trials performed with a population-based ADME simulator suggested that a minimal dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (>500 nM). Expand
Disposition of [1′-14C]Stavudine after Oral Administration to Humans
The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects. Before dosing humans with [1′-14C]stavudine, aExpand
Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate
TLDR
The biotransformation of norgestrel (NG) is elucidated, and it is found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm value of 1.57, which will lead to better understanding and management of NGMN-based drug-drug interactions when n orgestimate is coadministered with CYP 3A4 modulators. Expand
Cysteine Conjugate beta-Lyase-dependent Biotransformation of the Cysteine S-Conjugates of the Sevoflurane Degradation Product Compound A in Human, Nonhuman Primate, and Rat Kidney Cytosol and
TLDR
The presence of beta-lyase activity in human and rat kidney is confirmed and activity is also present in kidney tissue from nonhuman primates and compound A-derived conjugates 4 and 5 undergo beta-LYase-catalyzed biotransformation. Expand
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