Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.

Abstract

3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.

• Authors: Sunjoo Ahn, Jeffrey D Kearbey, Chien-Ming Li, Charles B Duke 3rd, Duane D Miller, James T Dalton
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 39 Issue 4 Pg. 636-43 (Apr 2011) ISSN: 1521-009X [Electronic] United States
• PMID: 21233217 (Publication Type: Journal Article)

Chemical References

• (3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antimitotic Agents
• Benzophenones
• Indoles
• NADP

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Antimitotic Agents (blood, chemical synthesis, metabolism, pharmacology)
• Benzophenones (blood, chemical synthesis, metabolism, pharmacology)
• Biotransformation
• Dogs
• Drug Stability
• Half-Life
• Haplorhini
• Humans
• Hydroxylation
• Indoles (blood, chemical synthesis, metabolism, pharmacology)
• Injections, Intravenous
• Metabolic Detoxication, Phase I
• Metabolic Detoxication, Phase II
• Mice
• Microsomes, Liver (drug effects, metabolism)
• NADP (metabolism)
• Rats
• Species Specificity
• Structure-Activity Relationship