Effect of extracellular water volume on the distribution kinetics of β-lactam antibiotics as a function of age

The distribution kinetics of cefazolin in rats has been examined at four different ages (1, 7, 50 and 100 weeks). The steady state distribution volume of cefazolin, estimated from the plasma time course after v. injection of 20 mg/kg, varied between 136 ml/kg (50-week-old rats) and 297 ml/kg (1-week-old rats). The extracellular fluid volume, obtained from the steady state distribution volume of inulin, varied between 126 ml/kg (50-week-old rats) and 370 ml/kg (1-week-old rats). There was a good correlation between the steady state distribution volume of cefazolin and extracellular fluid volume (r=0.977). The influence of changes on the value of the plasma unbound fraction and extracellular fluid volume on the tissue-to-plasma partition coefficient of β-lactam antibiotics was simulated by using a physiological pharmacokinetic model. The results of the simulation showed that extracellular fluid volume is an important factor affecting the distribution volume of β-lactam antibiotics and that plasma binding plays a minor role on it. The experimental and simulation results suggested that the change in the interstitial fluid volume is a determinant factor in the age-related changes in the distribution volume of β-lactam antibiotics.