Pharmacokinetics and Disposition of the Thiouracil Derivative PF-06282999, an Orally Bioavailable, Irreversible Inactivator of Myeloperoxidase Enzyme, Across Animals and Humans
| Autor: | Li Di, Bo Feng, Jennifer Q. Dong, Kazuko Sagawa, Tim F. Ryder, Manthena V.S. Varma, Steven G. Terra, Amit S. Kalgutkar, Angela Wolford |
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| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine Drug Evaluation Preclinical Administration Oral Biological Availability Pharmaceutical Science Pyrimidinones Pharmacology 030226 pharmacology & pharmacy Thiouracil Mice 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Pharmacokinetics Acetamides Animals Cytochrome P-450 Enzyme Inhibitors Humans Rats Wistar Peroxidase biology Chemistry Cytochrome P450 Haplorhini In vitro Rats Bioavailability HEK293 Cells 030104 developmental biology Intestinal Absorption Myeloperoxidase Renal physiology Hepatocytes Microsomes Liver biology.protein Microsome Female Caco-2 Cells Protein Binding |
| Zdroj: | Drug Metabolism and Disposition. 44:209-219 |
| ISSN: | 1521-009X |
| DOI: | 10.1124/dmd.115.067868 |
| Popis: | The thiouracil derivative PF-06282999 [2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide] is an irreversible inactivator of myeloperoxidase and is currently in clinical trials for the potential treatment of cardiovascular diseases. Concerns over idiosyncratic toxicity arising from bioactivation of the thiouracil motif to reactive species in the liver have been largely mitigated through the physicochemical (molecular weight, lipophilicity, and topological polar surface area) characteristics of PF-06282999, which generally favor elimination via nonmetabolic routes. To test this hypothesis, pharmacokinetics and disposition studies were initiated with PF-06282999 using animals and in vitro assays, with the ultimate goal of predicting human pharmacokinetics and elimination mechanisms. Consistent with its physicochemical properties, PF-06282999 was resistant to metabolic turnover from liver microsomes and hepatocytes from animals and humans and was devoid of cytochrome P450 inhibition. In vitro transport studies suggested moderate intestinal permeability and minimal transporter-mediated hepatobiliary disposition. PF-06282999 demonstrated moderate plasma protein binding across all of the species. Pharmacokinetics in preclinical species characterized by low to moderate plasma clearances, good oral bioavailability at 3- to 5-mg/kg doses, and renal clearance as the projected major clearance mechanism in humans. Human pharmacokinetic predictions using single-species scaling of dog and/or monkey pharmacokinetics were consistent with the parameters observed in the first-in-human study, conducted in healthy volunteers at a dose range of 20-200 mg PF-06282999. In summary, disposition characteristics of PF-06282999 were relatively similar across preclinical species and humans, with renal excretion of the unchanged parent emerging as the principal clearance mechanism in humans, which was anticipated based on its physicochemical properties and supported by preclinical studies. |
| Databáze: | OpenAIRE |
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