In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

Abstract

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

Keywords: Hypothermia; clearance; cytochrome P450; exposure; nimodipine; pharmacodynamics; pharmacokinetics.

Figure 1.

Mean plasma concentration–time profile of nimodipine in rabbits under normothermic and hypothermic conditions after single intravenous administration of nimodipine 0.5 mg/kg (mean ± SD, n = 5). ^aP < 0.05, ^bP < 0.01, vs. normothermia.

Figure 2.

Ultrasound image of cerebral blood flow in a rabbit under normothermic and hypothermic conditions. (a, c) Cerebral blood flow in normothermia (a) and hypothermia (c) before intravenous administration of nimodipine. (b, d) Cerebral blood flow in normothermia (b) and hypothermia (d) 10 min after administration of intravenous nimodipine.

Figure 3.

TAMX (a) and RI (b) of rabbits in normothermia or hypothermia (mean ± SD, n = 5). TAMX: time-averaged maximum velocity, RI: resistive index.

Figure 4.

Michaelis–Menten plot for the metabolism rate of nimodipine in rabbit liver microsomes at 28, 32 and 37℃. Each value is the mean ± SD of three experiments. Solid lines represent best fit: 28℃ (□), 32℃ (▴) and 37℃ (○).

Figure 5.

Uptake rate of nimodipine in rabbit hepatocytes at 28, 32 and 37℃. Values are the mean ± SD of three experiments: 28℃ (□), 32℃ (▴) and 37℃ (○).