We are performing mouse ES cell transplantation in parkinsonian rat. To avoid immune-rejection, we are daily injecting rats with cyclosporine (i.p.), according to routine protocols. After 6 weeks of treatments, we are wondering whether we can switch to an oral administration of cyclosporine (in drinking water). Thank you for your advice.
I would be very careful in changing since cyclosporine uptake, for what I know, depends from each animal water consumption, when administered in drinking water. Therefore this parameter could introduce several variations in your experimental conditions.
Anyway this paper may be helpful:
Jensen MB, Krishnaney-Davison R, Cohen LK, Zhang SC (2012) Injected Versus Oral Cyclosporine for Human Neural Progenitor Grafting in Rats. J Stem Cell Res Ther S10:003. doi:10.4172/2157-7633.S10-003
Assuming the animals are similar in size and activity, their water consumption should be within a similar range. So if you know average daily water consumption per animal and adjust drug per ml water to be above the minimal dose per kg but below toxicity that could potentially work. However the effect and toxicity of any drug depends on its absorption, tissue interaction, metabolism, and excretion - its pharmacokinetics. To be properly therapeutic, it is possible cyclosporin needs to have a peak level and then tail off in order to provide the desired suppressive effect on the immune system but not a toxic effect on other tissues such as the liver. This may only be possibly with a single daily injection. Steady oral administration would provide a lower peak but more stable level of drug- which may not be desirable. This would need to be ascertained. I also do not know the solubility of cyclosporine in water - you would need to be certain the drug stays in solution properly so all the animals received similar dosing.
Came across this dosing in a brief internet search. Continuous IV infusion is a delivery method therefore oral over the coarse of the day may be as well. It may be that the single oral solution dosing recommendation for pediatric patients is simply for more acceptance by the patient:
Usual Pediatric Dose for Organ Transplant - Rejection Prophylaxis
IV: 2 to 4 mg/kg/day IV infusion once a day over 4 to 6 hours or
1 to 2 mg/kg IV infusion twice a day over 4 to 6 hours or
2 to 4 mg/kg/day as a continuous IV infusion over 24 hours.
Capsules: 8 to 12 mg/kg/day orally in 2 divided doses.
Solution: 8 to 12 mg/kg orally once a day.
Doses are usually titrated downward with time to maintenance doses as low as 3 to 5 mg/kg/day. All doses should be adjusted to achieve the desired therapeutic concentration.
In my opinion the problem is switching from ip to oral administration since changes in cyclosporine bioavailability is strictly depending on the route of administration and on time
J Neurotrauma. 1996 May;13(5):267-72.
Alteration of cyclosporin-A pharmacokinetics after experimental spinal cord injury.
Ibarra A, Guízar-Sahagún G, Correa D, Kretschmer R, Grijalva I, Flores-Murrieta FJ, Castañeda-Hernández G, Odor A, López RM, Franco-Bourland R, Espitia AL, Salgado-Ceballos H, Madrazo I.
Hope it could help!
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