A clinical evaluation of the pharmacokinetics and pharmacodynamics of intravenous alfaxalone in cyclodextrin in male and female rats following a loading dose and constant rate infusion.
OBJECTIVE
To characterise, as a clinical study, the pharmacokinetics and pharmacodynamics and describe the hypnotic effect of the neurosteroid alfaxalone (3α-hydroxy-5 α-pregnane-11, 20-dione) formulated with 2-hydroxypropyl-β-cyclodextrin in male and female rats.


METHODS
Prospective, experimental laboratory study.


METHODS
A total of 12 (six male and six female) adult, aged-matched Sprague Dawley rats.


METHODS
Surgery and instrumentation was performed under isoflurane anaesthesia in an oxygen/nitrous oxide mixture (1:2) and local anaesthetic infiltration. All animals received a loading dose (1.67 mg kg-1minute-1) for 2.5 minutes followed by a constant rate infusion (0.75 mg kg-1minute-1) for 120 minutes of alfaxalone. Isoflurane and nitrous oxide was discontinued 2.5 minutes after the alfaxalone infusion started. Cardiorespiratory variables (heart rate, respiratory rate, arterial blood pressure and end tidal carbon dioxide tension) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Carotid artery blood samples were collected at strategic time points for blood gas analysis, haematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry.


RESULTS
There were significant differences between the sexes for plasma clearance (p=0.0008), half-life (p=0.0268) and mean residence time (p=0.027). Mean arterial blood pressure was significantly higher in the male rats (p=0.0255).


CONCLUSIONS
This study confirms that alfaxalone solubilised in 2-hydroxypropyl-β-cyclodextrin provides excellent total intravenous anaesthesia in rats. Sex-based differences in pharmacokinetics and pharmacodynamics were demonstrated and must be considered when designing biomedical research models using alfaxalone.
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK. Electronic address: Kate.White@nottingham.ac.uk.
Kate L
KL
White
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK.
Stuart
S
Paine
School of Biosciences, University of Nottingham, Sutton Bonington, UK.
John
J
Harris
D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011277:Pregnanediones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D056152:Respiratory Rate / Q000187:drug effects
D018686:Anesthetics, Intravenous; D014677:Pharmaceutical Vehicles; D011277:Pregnanediones; D002245:Carbon Dioxide; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C006477:alphaxalone
alfaxalone; anaesthetics; intravenous; rat; steroid