Pharmacokinetic and Metabolomic Studies with BIO 300, a Nanosuspension of Genistein, in a Nonhuman Primate Model

• Published in: International journal of molecular sciences Vol. 20; no. 5; p. 1231
• Main Authors: Cheema, Amrita K, Mehta, Khyati Y, Santiago, Paola T, Fatanmi, Oluseyi O, Kaytor, Michael D, Singh, Vijay K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12-03-2019; MDPI
• Subjects: Acute Radiation Syndrome - drug therapy; Acute Radiation Syndrome - metabolism; Amino acids; Animals; Antioxidants; BIO 300; Bioavailability; biomarkers; Bone marrow; Cell cycle; Chromatography, High Pressure Liquid - methods; DNA damage; Female; Genistein; Genistein - administration & dosage; Genistein - adverse effects; Genistein - pharmacokinetics; Granulocytes; Hematopoietic stem cells; Macaca mulatta; Male; Mass spectrometry; Metabolism; Metabolites; Metabolome - drug effects; Metabolomics; Metabolomics - methods; Nanoparticles - administration & dosage; Nanoparticles - adverse effects; Nanoparticles - metabolism; nonhuman primates; Pharmaceuticals; Pharmacokinetics; Primates; Public health; radiation countermeasure; Radiation effects; Scientific imaging; serum; Stem cell transplantation; Stem cells; Suspensions - administration & dosage; Suspensions - adverse effects; Suspensions - pharmacokinetics; Vital signs; United States > US; genistein; metabolomics; biomarkers; radiation countermeasure; nonhuman primates; serum; BIO 300
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20051231

Genistein is a naturally occurring phytoestrogen isoflavone and is the active drug ingredient in BIO 300, a radiation countermeasure under advanced development for acute radiation syndrome (H-ARS) and for the delayed effects of acute radiation exposure (DEARE). Here we have assessed the pharmacokinetics (PK) and safety of BIO 300 in the nonhuman primate (NHP). In addition, we analyzed serum samples from animals receiving a single dose of BIO 300 for global metabolomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS). We present a comparison of how either intramuscularly (
) or orally (
) administered BIO 300 changed the metabolomic profile. We observed transient alterations in phenylalanine, tyrosine, glycerophosphocholine, and glycerophosphoserine which reverted back to near-normal levels 7 days after drug administration. We found a significant overlap in the metabolite profile changes induced by each route of administration; with the
route showing fewer metabolic alterations. Taken together, our results suggest that the administration of BIO 300 results in metabolic shifts that could provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of BIO 300.