In Vivo Toxicity and Pharmacokinetic Features of the Janus Kinase 3 Inhibitor WHI-P131 [4-(4′Hydroxyphenyl)-Amino-6,7-Dimethoxyquinazoline]

• Published in: Clinical cancer research Vol. 5; no. 10; pp. 2954 - 2962
• Main Authors: UCKUN, F. M, EK, O, LIU, X.-P, CHEN, C.-L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.1999
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Medical sciences; Pharmacology. Drug treatments; Antineoplastic agent; Biological fluid; Animal model; Intraperitoneal administration; Intravenous administration; Rat; Toxicity; Monkey; Preclinical trial; Blood plasma; Lymphoproliferative syndrome; Established cell line; Primates; Acute lymphocytic leukemia; Tumor cell; Human; Enzyme; Transferases; Acute; Rodentia; Oral administration; Enzyme inhibitor; Malignant hemopathy; In vitro; Biological activity; Vertebrata; Chemotherapy; Mammalia; Mouse; Kinase; Animal; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265

4-(4′Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) is a potent and selective inhibitor of the Janus kinase 3, which triggers apoptosis in human acute lymphoblastic leukemia (ALL) cells. In this preclinical study, we evaluated the pharmacokinetics and toxicity of WHI-P131 in rats, mice, and cynomolgus monkeys. Following i.v. administration, the terminal elimination half-life of WHI-P131 was 73.2 min in rats, 103.4 min in mice, and 45.0 min in monkeys. The i.v. administered WHI-P131 showed a very wide tissue distribution in mice. Following i.p. administration, WHI-P131 was rapidly absorbed in both rats and mice, and the time to reach the maximum plasma concentration ( t max ) was 24.8 min in rats and 10.0 min in mice. Subsequently, WHI-P131 was eliminated with a terminal elimination half-life of 51.8 min in rats and 123.6 min in mice. The estimated i.p. bioavailability was 95% for rats, as well as for mice. WHI-P131 was quickly absorbed after oral administration in mice with a t max of 5.8 min, but its oral bioavailability was relatively low (29.6%). The elimination half-life of WHI-P131 after oral administration was 297.6 min. WHI-P131 was not acutely toxic to mice at single i.p. bolus doses ranging from 0.5–250 mg/kg. Two cynomolgus monkeys treated with 20 mg/kg WHI-P131 and one cynomolgus monkey treated with 100 mg/kg WHI-P131 experienced no side effects. Plasma samples from WHI-P131-treated monkeys exhibited potent antileukemic activity against human ALL cells in vitro . To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a Janus kinase 3 inhibitor. Further development of WHI-P131 may provide the basis for new and effective treatment programs for relapsed ALL in clinical settings.