A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach.

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations.

Esterase phenotyping in human liver in vitro: specificity of carboxylesterase inhibitors.

1. Esterases may play a major role in the clearance of drugs with functional groups amenable to hydrolysis, particularly in the case of ester prodrugs. To understand the processes involved in the elimination of such drugs, it is necessary to determine the esterases involved.

Absorption, distribution, metabolism, and excretion (ADME) of ¹⁴C-sonidegib (LDE225) in healthy volunteers.

Purpose: The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects.

Methods: Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.0 µCi) under fasting conditions.

Metabolism of patupilone in patients with advanced solid tumor malignancies.

A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression.

CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis.

Fingolimod (FTY720, Gilenya, 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol) is a novel drug recently approved in the United States for the oral treatment of relapsing multiple sclerosis. The compound is eliminated predominantly by ω-hydroxylation, followed by further oxidation. The ω-hydroxylation was the major metabolic pathway in human liver microsomes (HLM).

Absorption and disposition of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in healthy volunteers: a case of xenobiotic biotransformation following endogenous metabolic pathways.

Fingolimod [(FTY720), Gilenya; 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol], a new drug for the treatment of relapsing multiple sclerosis, acts through its phosphate metabolite, which modulates sphingosine 1-phosphate receptors. This represents a novel mechanism of action. In the present work, the absorption and disposition of (14)C-labeled fingolimod were investigated in healthy male volunteers after a single oral dose of 4.

The macrolide everolimus forms an unusual metabolite in animals and humans: identification of a phosphocholine ester.

The immunosuppressant macrolide everolimus was found to be metabolized in animals and humans to a phosphocholine ester (ATG181), a hitherto unknown type of conjugate in xenobiotic metabolism. The structure of ATG181 was elucidated by mass spectrometry and confirmed by synthesis. ATG181 was among the most prominent metabolites of everolimus in rat, monkey, and human blood and was found also in various tissues of the rat, whereas no ATG181 was identified in the urine and feces of the species investigated.

Pimecrolimus: skin disposition after topical administration in minipigs in vivo and in human skin in vitro.

The dermal disposition of pimecrolimus, a non-steroid, anti-inflammatory calcineurin inhibitor used for the treatment of atopic dermatitis, was evaluated in minipigs in vivo and in human skin in vitro using tritium-radiolabeled compound, and in dermal toxicokinetic investigations in minipigs using unlabeled compound. Following topical application of pimecrolimus 1% market form (MF) cream to minipig skin, approximately 2% of the dose penetrated into the stratum corneum and part of it into deeper skin layers. The remainder of the dose was recovered non-absorbed on the skin surface.

A microplate solid scintillation counter as a radioactivity detector for high performance liquid chromatography in drug metabolism: validation and applications.

Sensitive radioactivity detection following high performance liquid chromatography (HPLC) separation remains a challenge in many drug metabolism studies with radiolabeled compounds. In this work, solid scintillation counting (SSC) after fraction collection into 96-well plates was evaluated as an off-line radioactivity detection method, in comparison with conventional liquid scintillation counting (LSC). The impact of counting time and biological matrix on the quantification of radiolabeled metabolites and parent drug in samples from animal and human absorption, distribution, metabolism and excretion (ADME) studies was investigated.

Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro.

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed.

Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer.

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support.

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588.

A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.

One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1).

The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms.

Effect of Climbing Fibre Deprivation on the K+-evoked Release of Endogenous Adenosine from Rat Cerebellar Slices.

We report the identification of a compound whose K+-induced Ca2+-dependent release in rat cerebellar slices was reduced following climbing fibre deprivation by 3-acetylpyridine (3-AP) treatment. Based on HPLC retention time, UV absorption spectrum, and mass spectrometry, this compound was identified as adenosine. The K+-induced, Ca2+-dependent release of adenosine was subsequently quantified in control and 3-AP-treated rats.