Prediction of the pharmacokinetics of cefodizime and cefotetan in humans from pharmacokinetic parameters in animals.
Pharmacokinetic behavior of beta-lactam antibiotics (cefodizime and cefotetan) in humans were predicted from the animal data. Total body clearance (CLp) of these drugs in humans (weighting 65-69 kg) were successfully extrapolated from the allometric relationship between the clearance for the unbound drug in plasma and body weight (r = 0.954-1.000) with a power of 0.948-0.991 for cefodizime and 0.700-0.756 for cefotetan. We also predicted the volume of distribution at steady state (Vdss), the volume of distribution in the central compartment (V1) and the volume of distribution at beta-phase (Vd beta) of these drugs in humans from the observed human plasma unbound fraction, inasmuch as the plasma unbound fraction correlated well (r = 0.913-0.995) with the values of Vdss, V1, and Vd beta among various animal species. Based on these predicted pharmacokinetic parameters, we calculated the plasma concentration profiles of these drugs in humans and found a good agreement between the predicted and observed values. We also report here that the prediction is successful when we consider the plasma protein binding of these drugs.
Matsushita
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Suzuki
H
H
Sugiyama
Y
Y
Sawada
Y
Y
Iga
T
T
Hanano
M
M
Kawaguchi
Y
Y
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015313:Cefotetan / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding; D013045:Species Specificity
D001798:Blood Proteins; D015313:Cefotetan; D002439:Cefotaxime; C033356:cefodizime