Kalgutkar Amit S, Hatch Heather L, Kosea Frederick, Nguyen Hang T, Choo Edna F, McClure Kim F, Taylor Timothy J, Henne Kirk R, Kuperman Alexander V, Dombroski Mark A, Letavic Michael A
Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA.
Biopharm Drug Dispos. 2006 Nov;27(8):371-86. doi: 10.1002/bdd.520.
The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38alpha, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vd(ss)) ranging from 0.4-1.3 l/kg (2.4-26 l/m(2)) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m(2)) and Sprague-Dawley rats (7.65+/-1.08 ml/min/kg, 45.9+/-6.48 ml/min/m(2) in male rats and 3.15+/-0.27 ml/min/kg, 18.9+/-1.62 ml/min/m(2) in female rats) and moderate in beagle dogs (12.3+/-5.1 ml/min/kg, 246+/-102 ml/min/m(2)) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30-65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38alpha in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (f(u) approximately 0.1-0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC(50)>50 microM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent.
6-(4-(2,5-二氟苯基)恶唑-5-基)-3-异丙基-[1,2,4]-三唑并[4,3-a]吡啶(1)是一种有强效且具选择性的丝裂原活化蛋白(MAP)激酶p38α抑制剂，为支持其被选用于临床前安全性研究及潜在临床开发，对其在多个动物物种中的处置情况进行了表征。在所有受试物种中，1均表现出总体良好的药代动力学性质。静脉注射(i.v.)给药后，1在大鼠、犬和猴体内稳态分布容积(Vd(ss))较低，范围为0.4 - 1.3 l/kg(2.4 - 26 l/m²)。食蟹猴(6.00 ml/min/kg，72.0 ml/min/m²)和斯普拉格-道利大鼠(雄性大鼠为7.65±1.08 ml/min/kg，45.9±6.48 ml/min/m²；雌性大鼠为3.15±0.27 ml/min/kg，18.9±1.62 ml/min/m²)的全身血浆清除率较低，比格犬的清除率适中(12.3±5.1 ml/min/kg，246±102 ml/min/m²)，这使得临床前物种的血浆半衰期在1至5小时之间。口服(p.o.)给药后，在大鼠(30 - 65%)、犬(87%)和猴(40%)中观察到1具有中度至高的生物利用度，这与1在Caco - 2通透性试验中的体外吸收情况相符。在大鼠中，在所研究的剂量范围(5、50和100 mg/kg)内，口服药代动力学呈剂量依赖性。在大鼠、犬、猴和人肝微粒体以及临床前物种体内，1的主要清除途径涉及细胞色素P450酶介导的氧化代谢。在临床前物种和人体内，1的主要代谢途径是异丙基发生羟基化生成叔醇代谢物2。从使用同工酶特异性抑制剂和重组CYP酶进行的反应表型分析判断，在人肝微粒体中，这种转化由CYP3A4催化。在各种体外试验中，代谢物2也显示出对p38α具有抑制活性。在大鼠、小鼠、犬、猴和人体内，1以及活性代谢物2与血浆蛋白的结合程度为中度至高(f(u)约为0.1 - 0.33)。1以及活性代谢物2对五种主要细胞色素P450酶即CYP1A2、2C9、2C19、2D6和3A4均未表现出竞争性抑制(IC₅₀>50 μM)。总体而言，这些结果表明1在临床前物种中的吸收、分布、代谢和排泄(ADME)情况相对一致，并预测其在人体内可能具有良好的药代动力学性质，支持其被选用于毒性/安全性评估研究以及作为抗炎剂在人体中进行可能的研究。
