*3.3. Group SC*

The rats weighed 317.9 ± 19.9 g (*n* = 7). Data from one rat (the first) was excluded from the study as it was administered an initial SC dose of medetomidine of 0.1 mg/kg and became apnoeic for approximately 2 min, requiring external chest compressions. The seven subsequent rats were administered a lower dose of 0.05 mg/kg SC medetomidine and anaesthesia was uneventful. The blood glucose concentration peaked at 120 min at 20.4 ± 3.4 mmol/L (Figure 1).

The inhaled isoflurane concentration required to maintain an adequate depth of anaesthesia throughout the procedure in Group SC was more variable than in the other groups (Table 1). The serum medetomidine concentration peaked at 60 min at 3.4 ± 0.9 ng/mL (Figure 2).

**Figure 2.** Time course of mean (±standard deviation) serum medetomidine concentration after subcutaneous administration of 0.05 mg/kg medetomidine in six Sprague-Dawley rats.

### *3.4. Pharmacokinetic Calculations*

The pharmacokinetic and pharmacodynamic parameters were calculated from the mean serum medetomidine concentration data (Table 2). To achieve a target medetomidine concentration of 14.4 ± 3.0 ng/mL an initial SC dose of 0.12 mg/kg medetomidine followed by a SC infusion of 0.08 mg/kg/h medetomidine should be administered during isoflurane anaesthesia.

**Table 2.** Individual and mean (±standard deviation) pharmacokinetic (PK) and pharmacodynamic parameters after administration of 0.05 mg/kg SC medetomidine in seven Sprague-Dawley rats. *Cmax* = maximum serum concentration; *tmax* = time of *Cmax*; λz = elimination rate constant; *t1*/*2*β = elimination half-life; *AUC0*→∞ = area under the serum concentration time curve from time = 0 to ∞; *Cl* = total body clearance; *Vdarea* = volume of distribution at pseudo-equilibrium; LD = loading dose; MD = maintenance dose.


### *3.5. Trial of Results*

Two additional rats were administered medetomidine with isoflurane at the doses calculated in this study. The vapouriser setting for isoflurane could be maintained at or below 0.5% and anaesthesia was uneventful. Given the calculated initial dose was higher than that used in groups SC and IV the

initial dose was administered over five seconds to mitigate the risk of apnoea (as observed in the IV group and the first rat in the SC group that was administered 1.0 mg/kg SC). Apnoea did not occur when the initial dose was delivered over five seconds.
