Progesterone pharmacokinetics in the mouse: implications for potential stroke therapy.
OBJECTIVE
Progesterone has been shown to be neuroprotective in a number of preclinical central nervous system injury models including cerebral ischaemia. The aim of this study was to clarify differences in outcomes owing to different dosing regimens and the pharmacokinetic profile of progesterone, particularly in relation to brain levels.


METHODS
Male C57 Bl/6 mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide) or with a bolus injection followed by continuous subcutaneous infusion (1.0 µl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Plasma and brain samples were collected over 24 h from bolus-injected mice and 48 h from mice implanted with minipumps. Progesterone concentrations were measured by an enzyme-linked immunoassay and pharmacokinetic profiles were constructed.


RESULTS
Intraperitoneally injected progesterone had a short half-life (fast component half-life of 0.2 h) in both plasma and brain. Minipump delivery resulted in higher concentrations of progesterone in plasma and particularly in brain over a longer period. The volume of distribution with intraperitoneal injection was 172.78 versus 1641.84 ng/h per g via minipump in the first 24 h.


CONCLUSIONS
A bolus intraperitoneal loading dose of progesterone followed by continuous delivery via osmotic minipump is an effective way of delivering progesterone to the brain.
Division of Stroke, University of Nottingham, Clinical Sciences Building, City Hospital Campus School of Biomedical Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, UK. msxrw@nottingham.ac.uk
Raymond
R
Wong
David
D
Ray
David A
DA
Kendall
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011374:Progesterone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020521:Stroke / Q000188:drug therapy; D013997:Time Factors; D014018:Tissue Distribution
D018696:Neuroprotective Agents; D011374:Progesterone; D004121:Dimethyl Sulfoxide