title: The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents.
abstract: The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.
authors.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. m.bull@auckland.ac.nz.|Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand. m.bull@auckland.ac.nz.
authors.forename: M R
authors.initials: MR
authors.lastname: Bull
authors.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: J A
authors.initials: JA
authors.lastname: Spicer
authors.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.|Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland.
authors.forename: K M
authors.initials: KM
authors.lastname: Huttunen
authors.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Ciccone
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Browne
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, VIC, 3002, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3052, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Faculty of Medical and Health Sciences, Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.|Faculty of Medical and Health Sciences, Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
authors.forename: N A
authors.initials: NA
authors.lastname: Helsby
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D054353:Perforin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D054353:Perforin
keywords: Immunosuppressive; Mouse; Perforin; Pharmacokinetics