PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR CEFAZOLIN IN RABBITS AND ITS PRELIMINARY EXTRAPOLATION TO MAN

Google Scholar
  • 1 January 1985
    • journal article
    • research article
    • Vol. 13  (6) , 729-739
Abstract
In the present study, the physiologically based pharmacokinetic model, which succceeded previously in predicting the pharmacokinetics of .beta.-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C. H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for .beta.-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and insulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period of the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.

This publication has 15 references indexed in Scilit: