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.
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Acknowledgments
This work was supported by the Wellcome Trust (Grant 092717) and the Auckland Division of the Cancer Society of New Zealand. MR Bull thanks the Maurice Wilkins Centre (Auckland, New Zealand) and the School of Medical Sciences PBRF publication bursary (The University of Auckland) for financial support. We also thank Sisira Kumara for the HPLC and solubility studies.
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13318_2014_220_MOESM2_ESM.tif
Plasma concentration-time profiles following administration of 16 compounds at 5 mg/kg i.v. injection to male CD-1 mice. The mean ± standard deviation data from pooled samples from individual mice (n=3) at each time point are shown. Error bars may be smaller than the symbol. The two-compartment model fit of the data derived using Phoenix WinNonlin 6.2 (Pharsight Corporation, St. Louis, MO) are shown. The line indicates target IC50 values from in vitro activity assays (Spicer et al. 2012; Spicer et al. 2013) (TIFF 1098 kb)
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Bull, M.R., Spicer, J.A., Huttunen, K.M. et al. The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents. Eur J Drug Metab Pharmacokinet 40, 417–425 (2015). https://doi.org/10.1007/s13318-014-0220-y
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DOI: https://doi.org/10.1007/s13318-014-0220-y