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Study of Jadomycin Pharmacokinetics in Balb/C Mice
Author(s) -
Relja Nicholas,
Hall Steven R.,
Sleno Lekha,
Bennett Leah,
MacLeod Jeanna,
MartinezFarina Camilo F.,
Jakeman David L.,
Goralski Kerry B.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1064.8
Subject(s) - pharmacokinetics , pharmacology , distribution (mathematics) , absorption (acoustics) , kidney , chemistry , medicine , mathematical analysis , physics , mathematics , acoustics
Background Jadomycins are natural product molecules derived from the soil bacteria Streptomyces venezuelae ; jadomycins maintain their cytotoxicity in multidrug resistant (MDR) human and mouse breast cancer cell lines that overexpress ATP‐binding cassette (ABC) transporters. While effective in in vitro assays, jadomycins have not been studied in animal models. Objective To conduct the first in animal pharmacokinetic and safety studies of jadomycins B, S, and F in male and female Balb/C mice. Methods Jadomycins were administered intraperitoneally (IP) to male and female Balb/C mice at a 6mg/kg dose. In one group of mice (n = 5) up to four repeated saphenous vein blood samples (40 mL) were obtained after 15, 30, 60, and 90 minutes with terminal blood collection occurring at 120 minutes in order to characterize absorption and distribution phases. In a second group of mice saphenous vein blood samples were obtained at 2, 4, 6, 8 and 10 hours to characterize terminal elimination. Liver, kidney, lung and brains were collected after 2 hours and then at 8 or 10 hours (males and females respectively) to characterize jadomycin distribution to these tissues. Serum and tissue samples underwent extraction and jadomycin concentrations were then determined by mass spectrometry. Results The concentration versus time profiles of jadomycins B, S and F were similar. They were absorbed rapidly after IP injection with peak concentrations in the 1–10 mM range observed after 15 minutes. This was followed by a rapid distribution phase (t 1/2 a = 20 – 40 min) and a slower terminal elimination (t 1/2 b = 1.5 – 2 hours). Jadomycins accumulated in the liver > kidney > lung and were not detectable in the brain. No metabolites were detected and no acute toxicity responses were observed. Conclusions These 1 st in vivo studies of jadomycins reveal that jadomycins are safe at a 6 mg/kg IP dose and achieve concentrations in mouse serum that are above the IC50s (1–4 μM) for human and mouse breast cancer cells in vitro. Our results indicate that jadomycins are rapidly eliminated as unchanged drug and that two to three times daily dosing will be required for future tumor studies. Support or Funding Information Cancer Research Training Program (CRTP) through Beatrice Hunter Cancer Research Institute, Canadian Breast Cancer Foundation Atlantic (CBCF), Nova Scotia Health Research Foundation (NSHRF), and Dalhousie University