title: Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice.
abstract: There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2-32,400 ng/mL in plasma, 16.2-6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4-6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from -8.50 to 13.92%. The relative recoveries were 85.6-113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Nag
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.forename: Sukesh
authors.initials: S
authors.lastname: Voruganti
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
authors.forename: Horrick
authors.initials: H
authors.lastname: Sharma
authors.forename: Shivaputra
authors.initials: S
authors.lastname: Patil
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C000593082:6-methoxy-1-(naphthalen-1-yl)-9H-pyrido(3,4-b)indole; D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines
keywords: HPLC; SP-141; pharmacokinetics; pyrido[b]indole