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1.
Drug Metab Dispos ; 43(2): 289-97, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25488930

ABSTRACT

The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of ¹4C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC(0-24 h) and AUC(0-72 h), respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Intestinal Absorption , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Adenine/analysis , Adenine/blood , Adenine/urine , Administration, Oral , Adult , Agammaglobulinaemia Tyrosine Kinase , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/analysis , Biotransformation , Carbon Radioisotopes , Feces/chemistry , Half-Life , Humans , Hydrolysis , Hydroxylation , Intestinal Elimination , Male , Metabolic Clearance Rate , Middle Aged , Oxidation-Reduction , Piperidines , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/analysis , Protein-Tyrosine Kinases/metabolism , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/analysis , Pyrazoles/blood , Pyrazoles/urine , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/analysis , Renal Elimination
2.
Anal Chem ; 84(5): 2395-401, 2012 Mar 06.
Article in English | MEDLINE | ID: mdl-22304524

ABSTRACT

During the development of a new drug compound, its metabolism needs to be unraveled. For quantification of the metabolites formed, the drug under investigation is traditionally synthesized with a radiolabel ((14)C or (3)H) and the metabolites present in different matrixes (blood, urine, feces) upon drug administration are determined by means of high-performance liquid chromatography (HPLC) coupled to radiodetection. This approach allows for quantification of the metabolites formed and enables a straightforward distinction between exogenous (i.e., drug-related) and endogenous species (as only the radiolabeled species are detected). However, in some cases, the use of a radiolabeled compound in human in vivo studies is not advisible, e.g., for drug compounds or their metabolites showing a long plasma or tissue half-life. In cases where the candidate drug molecule contains an element detectable by means of inductively coupled plasma mass spectrometry (ICP-MS), HPLC/ICP-MS is a promising alternative approach. However, the method lacks specificity when a distinction between drug-related species and endogenous compounds containing the same target element needs to be accomplished. As a result, we have developed an HPLC/ICP-MS-based method combined with "reverse" online isotope dilution ("reverse" online ID) for metabolite quantification. The methodology was evaluated by the analysis of feces samples from rats dosed with a (81)Br-labeled drug compound. The method allows for both (i) valid quantification of the drug metabolites and (ii) distinction among endogenous, exogenous, and "mixed" species, based on their isotopic "fingerprint". A good repeatability (relative standard deviation of 4.2%) and limit of detection (0.35 mg of drug compound L(-1) of feces extract), of the same order of magnitude as those observed for "normal" online ID HPLC/ICP-MS and HPLC/radiodetection, were achieved.


Subject(s)
Chromatography, High Pressure Liquid , Pharmaceutical Preparations/analysis , Spectrometry, Mass, Electrospray Ionization , Animals , Antitubercular Agents/analysis , Antitubercular Agents/metabolism , Bromine/chemistry , Carbon Radioisotopes/chemistry , Feces/chemistry , Humans , Isotope Labeling , Isotopes/chemistry , Pharmaceutical Preparations/metabolism , Rats , Tritium/chemistry
3.
Anal Bioanal Chem ; 402(1): 439-48, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21877185

ABSTRACT

The aim of this work was speciation analysis of metabolites in feces samples collected within a clinical study during which a bromine-containing anti-tuberculosis drug (TMC207) was administered to patients with multi-drug resistant tuberculosis infection. Owing to slow elimination of the drug, no (14)C label was used within this study. Quantification of the bromine species was accomplished using high performance liquid chromatography coupled to inductively coupled plasma-mass spectrometry (HPLC/ICP-MS) in combination with on-line isotope dilution (on-line ID), while structural elucidation of the species was performed using HPLC coupled to electrospray ionization-mass spectrometry. The ICP-MS-based method developed shows a good intra- and inter-day reproducibility (relative standard deviation = 3.5%, N = 9); the limit of detection (1.5 mg TMC207 L(-1)) is of the same order of magnitude as that for HPLC/radiodetection; the dynamic range of the method covers more than two orders of magnitude. Furthermore, the column recovery was demonstrated to be quantitative (recoveries between 90.6% and 99.5%). Based on the excellent figures of merit, the "cold" HPLC/ICP-MS approach could be deployed for the actual human in vivo metabolism study, such that exposure of the human volunteers to the (14)C radiolabel was avoided.


Subject(s)
Antitubercular Agents/metabolism , Feces/chemistry , Quinolines/metabolism , Tuberculosis, Multidrug-Resistant/drug therapy , Antitubercular Agents/analysis , Antitubercular Agents/therapeutic use , Bromine/analysis , Carbon Radioisotopes/administration & dosage , Carbon Radioisotopes/analysis , Chromatography, High Pressure Liquid/methods , Diarylquinolines , Female , Humans , Indicator Dilution Techniques , Isotopes/analysis , Male , Quinolines/analysis , Quinolines/therapeutic use , Spectrometry, Mass, Electrospray Ionization/methods
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